Methods, treatment, and compositions for characterizing thyroid nodule

ABSTRACT

The current disclosure provides, inter alia, method of determining benign nodules from thyroid cancer in a subject that is found to have a thyroid nodule, method of treating thyroid cancer in a subject detected to have thyroid cancer by the method of the current disclosure, compositions for determining benign nodules from thyroid cancer in a subject, and kits including reagents and composition for determining benign nodules from thyroid cancer in a subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Pat. Application No.15/217,645, filed Jul. 22, 2016, now U.S. Pat. No. 11,505,829, issued onNov. 22, 2022, which claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62/196,678, filed Jul. 24,2015, the content of which are incorporated herein by reference in theirentireties.

INCORPORATION-BY-REFERENCE OF SEQUENCE LISTING

The content of the XML file named“048440-573C01US_Sequence_Listing.xml”, which was created on Dec. 2,2022, and is 22,950 kilobytes in size, is hereby incorporated byreference in its entirety.

BACKGROUND OF THE DISCLOSURE

Palpable thyroid nodules are typically detected in 2-6% of thepopulation, and this increases to 19-35% with ultrasound detection (DeanDS and Gharib H. Best Pract Res Clin Endocrinol Metab 2008; 22:901-11).Approximately 5-15% of thyroid nodules are found to be thyroid cancer,making the existence of a nodule clinically relevant. Fine needleaspiration (FNA) with cytology is currently the standard diagnosticprocedure used to evaluate thyroid nodules. However, in as many as 30%of cases, the cytological diagnosis is indeterminate because ofcytological features that overlap between benign and malignant nodules.For most indeterminate cases half or the entire thyroid is resected, yetas many as 80% of these cases are found to be benign.

Most thyroid nodules do not cause symptoms. Often, thyroid nodules arediscovered incidentally during a routine physical examination or onimaging tests like CT scans or neck ultrasound done for completelyunrelated reasons. Occasionally, patients themselves find thyroidnodules by noticing a lump in their neck while looking in a mirror,buttoning their collar, or fastening a necklace. Abnormal thyroidfunction tests may occasionally be the reason a thyroid nodule is found.Thyroid nodules may produce excess amounts of thyroid hormone causinghyperthyroidism. However, most thyroid nodules, including those thatcancerous, are actually non-functioning, meaning current diagnostic testreadouts such as the level of Thyroid-Stimulating Hormone (TSH) arenormal. Rarely, patients with thyroid nodules may complain of pain inthe neck, jaw, or ear. If a nodule is large enough to compress thewindpipe or esophagus, it may cause difficulty with breathing,swallowing, or cause a “tickle in the throat”. Even less commonly,hoarseness can be caused if the nodule invades the nerve that controlsthe vocal cords but this is usually related to thyroid cancer.

Molecular testing is a potential alternative to cytopathologicalexamination. However, FNA molecular testing based on DNA mutationsfrequently fails. There are two major reasons for this failure: (i) notall papillary thyroid carcinoma (PTC) specimens are characterized by acommon set of cancer associated mutations, and (ii) cancer associatedmutations like KRAS are frequently found in benign thyroid nodule (BTN)specimens. At the same time commercial diagnostic tests for FNA based ontranscriptional activity and currently implemented in clinical practiceis complicated due to RNA instability and associated with only anapproximately 50% positive predictive value. Thus, there is an urgentneed for highly sensitive, low cost biomarker panels that can accuratelydiagnose thyroid nodules from FNA biopsies.

BRIEF SUMMARY OF THE DISCLOSURE

The present subject matter provides, inter alia, a method of determiningbenign nodules from thyroid cancer in a subject that is found to have athyroid nodule, a method of treating thyroid cancer in a subjectdetected to have thyroid cancer, compositions for determining benignnodules from thyroid cancer in a subject, and kits including reagentsand compositions for determining benign nodules from thyroid cancer in asubject.

In embodiments, aspects of the present subject matter provide a methodof detecting methylation or unmethylation of a thyroid nodule DNA of asubject, the method including: (i) isolating DNA from a thyroid noduleof the subject thereby forming isolated thyroid nodule DNA, (ii)contacting the isolated thyroid nodule DNA with a bisulfite salt (suchas sodium bisulfite) thereby forming a reacted thyroid nodule DNA, (iii)detecting the presence or absence of uracil in the reacted thyroidnodule DNA at a methylation site set forth in Table 1, thereby detectingmethylation or unmethylation of the thyroid nodule DNA of the subject.

Also provided is a method of determining a thyroid cancer or risk ofdeveloping thyroid cancer in a subject in need thereof. The methodincludes isolating DNA from a thyroid nodule of the subject therebyforming isolated thyroid nodule DNA. The isolated thyroid nodule DNA iscontacted with sodium bisulfite thereby forming a reacted thyroid noduleDNA. The presence or absence of uracil is detected in the reactedthyroid nodule DNA at a methylation site set forth in Table 1 therebydetermining thyroid cancer in the subject.

In embodiments, provided herein is a method of treating thyroid cancerin a subject by administering to the subject an active agent fortreating thyroid cancer. The method includes identifying the subject fortreatment by a method including isolating DNA from a thyroid nodule ofthe subject thereby forming isolated thyroid nodule DNA. The isolatedthyroid nodule DNA is contacted with sodium bisulfite thereby forming areacted thyroid nodule DNA. The presence or absence of uracil in thereacted thyroid nodule DNA is detected at a methylation site set forthin Table 1 thereby determining thyroid cancer in the subject.

Also included herein is a deoxyribonucleic acid 5 to 100, 5 to 200, 5 to300, or at least about 5, 50, 100, 150, 200, 250, 300, or morenucleotides in length including a uracil-containing sequence identicalto at least a 5 contiguous nucleotides within a sequence including SEQID NO:1 to SEQ ID NO:550.

In embodiments, provided herein is an oligonucleotide 5 to 100, 5 to200, 5 to 300, or at least about 5, 50, 100, 150, 200, 250, 300, or morenucleotides in length including identical or complementary to at least5, 10, 20, 25, 50, 100, 150, 200, 250, or 300 contiguous nucleotideswithin a sequence including SEQ ID NO:1 to SEQ ID NO:550.

Aspects of the present subject matter also include a deoxyribonucleicacid including SEQ ID NO: 551 to SEQ ID NO: 782, in which the nucleicacid is hybridized to a complementary DNA sequence having uridine orcytosine.

Also provided is a kit including a plurality (e.g., at least about 10,20, 40, 50, 100, 150, 200, 225, or 232) nucleic acids each independentlycomprising SEQ ID NO: 551 to SEQ ID NO: 782, in which the nucleic acidsdo not simultaneously include the same sequence of SEQ ID NO: 551 to SEQID NO: 782.

Aspects of the present subject matter also provide a system fordetecting methylation or unmethylation of a thyroid noduledeoxyribonucleic acid (DNA) of a subject. The system can include atleast one processor; and at least one memory including program codewhich when executed by the at least one memory provides operations. Theoperations can include: isolating DNA from a thyroid nodule of thesubject thereby forming isolated thyroid nodule DNA; contacting theisolated thyroid nodule DNA with bisulfite salt thereby forming areacted thyroid nodule DNA; detecting a presence or absence of uracil inthe reacted thyroid nodule DNA at a plurality of methylation sites setforth in Table 1, thereby detecting methylation or unmethylation of thethyroid nodule DNA of the subject; and generating a diagnosis for thesubject based at least in part on the presence or absence of uracil inthe reacted thyroid nodule DNA at the plurality of methylation sites setforth in Table 1; and providing, via a user interface, the diagnosis forthe subject.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B show a drawing defining a threshold for thyroid adenomaspecific signature for individula cytosine regions. FIG. 1A: Adenomaspecific hypomethylation signature. FIG. 1B: Adenoma specifichypermethylation signature.

FIGS. 2A and 2B show 364 cytosines associated with BTN or PTC specificDNA methylation changes. Legend (FIG. 2A): Cancer specific signature(gray); benign specific signature (black). FIG. 2B: 364 CpG sitesassociated with benign- and thyroid cancer-specific DNA methylationchanges. Each row represents a single cytosine. Each column representstissue specimen. Dark gray, light gray and black indicate high, low andmedium levels of DNA methylation, respectively. Abbreviation “A” is forthyroid benign nodule and “T” is for thyroid cancer.

FIGS. 3A-3C depict exemplary thyroid cancer diagnostics based on DNAmethylation signatures. FIG. 3A: Thyroid cancer diganostics based onbenign DNA methylation signature, cancer DNA methylation signature andcancer risk scores. FIG. 3B: DNA methylation signatures for malignantand benign thyroid nodules according to leave one-out-cross-validationtechnique. Specimenswith indeterminate epigenetic signature areunderlined. Abbreviation “A” is for thyroid benign nodule and “T” is forthyroid cancer. FIG. 3C: Algorithm for the diagnosis prediction based onBTN, PTC and cancer risk scores.

FIG. 4 depicts a block diagram illustrating an exemplary thyroid cancerdiagnostics system.

FIG. 5 depicts a flowchart illustrating an exemplary process fordiagnosing thyroid cancer.

FIG. 6 depicts a flowchart illustrating an exemplary process fordiagnosing thyroid cancer.

DETAILED DESCRIPTION OF THE DISCLOSURE

Provided herein are, inter alia, compositions, methods, kits, andsystems for detecting unmethylated DNA. In embodiments, compositions,methods, kits, and systems for detecting unmethylated DNA from thyroidnodule are included herein.

The following definitions are included for the purpose of understandingthe present subject matter and for constructing the appended patentclaims. Abbreviations used herein have their conventional meaning withinthe chemical and biological arts.

Definitions

The term “thyroid nodule” is used according to its plain ordinarymeaning and refers to an abnormal growth of thyroid cells. The abnormalgrowth may form, for example, a mass or lump within or on the thyroidgland. The mass or lump may be fluid- filled or solid. The thyroidnodules may be benign (noncancerous) or cancerous.

Thyroid fine needle aspiration biopsy (FNA or FNAB): For a fine needlebiopsy, a needle is used to withdraw cells from a thyroid nodule. Inembodiments, several samples are taken from different parts of thenodule, e.g., to increase the chance of finding cancerous cells if theyare present. In embodiments, a sample is taken from one part of thenodule. In embodiments, examination of the cells under a microscope isnot necessary. In non-limiting examples, the needle used for FNA is a20-35 gauge needle (such as a 23, 24 or 25 gauge needle).

The term “disease” refers to any deviation from the normal health of amammal and includes a state when disease symptoms are present, as wellas conditions in which a deviation (e.g., infection, gene mutation,genetic defect, etc.) has occurred, but symptoms are not yet manifested.According to the present disclosure, the methods disclosed herein aresuitable for use in a patient that is a member of the Vertebrate class,Mammalia, including, without limitation, primates, livestock anddomestic pets (e.g., a companion animal). Typically, a patient will be ahuman patient. As used herein, a “symptom” of a disease includes andclinical or laboratory manifestation associated with the disease, and isnot limited to what a subject can feel or observe.

The terms “subject,” “patient,” “individual,” and the like as usedherein are not intended to be limiting and can be generallyinterchanged. That is, an individual described as a “patient” does notnecessarily have a given disease, but may be merely seeking medicaladvice.

The term “subject” as used herein includes all members of the animalkingdom that may suffer from the indicated disorder. In some aspects,the subject is a mammal, and in some aspects, the subject is a human.

It must be noted that as used herein and in the appended embodiments,the singular forms “a,” “an,” and “the” include the plural referenceunless the context clearly dictates otherwise. Thus, for example, areference to “a disease,” “a disease state”, “a nucleic acid” or “a CpGsite” is a reference to one or more such embodiments, and includesequivalents thereof known to those skilled in the art and so forth.

Throughout the description and claims of this specification the word“comprise” and other forms of the word, such as “comprising” and“comprises,” means including but not limited to, and is not intended toexclude, for example, other components.

A “control” sample or value refers to a sample that serves as areference, usually a known reference, for comparison to a test sample.For example, a test sample can be taken from a patient suspected or atrisk of having thyroid cancer and compared to samples from a knownthyroid cancer patient, or a known normal (non-disease) individual. Acontrol can also represent an average value gathered from a populationof similar individuals, e.g., thyroid cancer patients or healthyindividuals with a similar medical background, same age, weight, etc. Acontrol value can also be obtained from the same individual, e.g., froman earlier-obtained sample, prior to disease, or prior to treatment. Oneof skill will recognize that controls can be designed for assessment ofany number of parameters.

One of skill in the art will understand which controls are valuable in agiven situation and be able to analyze data based on comparisons tocontrol values. Controls are also valuable for determining thesignificance of data. For example, if values for a given parameter arewidely variant in controls, variation in test samples will not beconsidered as significant.

The term “diagnosis” refers to a relative probability that a disease ispresent in the subject. Similarly, the term “prognosis” refers to arelative probability that a certain future outcome may occur in thesubject. For example, in the context of the present disclosure,prognosis can refer to the likelihood that an individual will develop adisease, or the likely severity of the disease (e.g., severity ofsymptoms, rate of functional decline, survival, etc.). The terms are notintended to be absolute, as will be appreciated by any one of skill inthe field of medical diagnostics.

“Nucleic acid” or “oligonucleotide” or “polynucleotide” or grammaticalequivalents used herein means at least two nucleotides covalently linkedtogether. Oligonucleotides are typically from about 5, 6, 7, 8, 9, 10,12, 15, 25, 30, 40, 50 or more nucleotides in length, up to about 100nucleotides in length. Nucleic acids, including ribonucleic acids (RNA)and deoxyribonucleic acids (DNA), and polynucleotides are a polymers ofany length, including longer lengths, e.g., 200, 300, 500, 1000, 2000,3000, 5000, 7000, 10,000, etc. A nucleic acid of the present inventionwill generally contain phosphodiester bonds, although in some cases,nucleic acid analogs are included that may have alternate backbones,comprising, e.g., phosphoramidate, phosphorothioate, phosphorodithioate,or O-methylphophoroamidite linkages (see Eckstein, Oligonucleotides andAnalogues: A Practical Approach, Oxford University Press); and peptidenucleic acid backbones and linkages. Other analog nucleic acids includethose with positive backbones; non-ionic backbones, and non-ribosebackbones, including those described in U.S. Pat. Nos. 5,235,033 and5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CarbohydrateModifications in Antisense Research, Sanghui & Cook, eds. Nucleic acidscontaining one or more carbocyclic sugars are also included within onedefinition of nucleic acids. Modifications of the ribose-phosphatebackbone may be done for a variety of reasons, e.g., to increase thestability and half-life of such molecules in physiological environmentsor as probes on a biochip. Mixtures of naturally occurring nucleic acidsand analogs can be made; alternatively, mixtures of different nucleicacid analogs, and mixtures of naturally occurring nucleic acids andanalogs may be made.

The term “bp” and the like refer, in the usual and customary sense, tothe indicated number of base pairs.

The terms “identical” or percent “identity,” in the context of two ormore nucleic acids (e.g., genomic sequences or subsequences or codingsequences) or polypeptide sequences, refer to two or more sequences orsubsequences that are the same or have a specified percentage of aminoacid residues or nucleotides that are the same (i.e., 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, or more identity over a specified region), when compared andaligned for maximum correspondence over a comparison window, ordesignated region as measured using one of the following sequencecomparison algorithms or by manual alignment and visual inspection. Suchsequences are then said to be “substantially identical.” This definitionalso refers to the compliment of a test sequence. Optionally, theidentity exists over a region that is at least about 10 to about 100,about 20 to about 75, about 30 to about 50 amino acids or nucleotides inlength.

An example of algorithms suitable for determining percent sequenceidentity and sequence similarity are the BLAST and BLAST 2.0 algorithms,which are described in Altschul et al., Nuc. Acids Res. 25:3389-3402(1977) and Altschul et al., J. Mol. Biol. 215:403-410 (1990),respectively. As will be appreciated by one of skill in the art, thesoftware for performing BLAST analyses is publicly available through thewebsite of the National Center for Biotechnology Information.

A “label” or a “detectable moiety” is a composition detectable byspectroscopic, photochemical, biochemical, immunochemical, chemical, orother physical means. For example, useful labels include ³²P,fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonlyused in an ELISA), biotin, digoxigenin, or haptens and proteins or otherentities which can be made detectable, e.g., by incorporating aradiolabel into a peptide or antibody specifically reactive with atarget peptide. Any method known in the art for conjugating an antibodyto the label may be employed, e.g., using methods described inHermanson, Bioconjugate Techniques 1996, Academic Press, Inc., SanDiego.

The term “associated” or “associated with” in the context of a substance(e.g., level of uracil or methylation level in a thyroid nodule) doesnot necessarily mean that the disease is caused by (in whole or inpart), or a symptom of the disease is caused by (in whole or in part)the substance or substance activity or function (i.e., level of uracilin the regions of chromosomes assayed).

The term “unmethylated DNA” or “demethylated DNA” means DNA that lacks amethyl group conjugated to cytosine in a segment of the DNA. DNAmethylation typically occurs in a CpG dinucleotide context. DNAmethylation at the 5′ position of cytosine may have the specific effecton gene expression in vivo. DNA methylation may also form the basis ofepigenetic structure, which typically enables a single cell to grow intomultiple organs or perform multiple functions.

The CpG sites or CG sites are regions of DNA where a cytosine nucleotideoccurs next to a guanine nucleotide in the linear sequence of basesalong its length. “CpG” is shorthand for “—C—phosphate—G—”, that is,cytosine and guanine separated by only one phosphate; phosphate linksany two nucleosides together in DNA. The “CpG” notation is used todistinguish this linear sequence from the CG base-pairing of cytosineand guanine. The CpG notation can also be interpreted as the cytosinebeing 5′ prime to the guanine base.

In embodiments, methylation is detected based on a chemical reaction ofsodium bisulfite with DNA that converts unmethylated cytosines of CpGdinucleotides to uracil or UpG. However, methylated cytosine is notconverted in this process, the methods described herein allowdetermination of methylation status as methylated or unmethylated.

Evaluation of Thyroid Fine Needle Biopsies by Visual Examination

Cells in a thyroid vine needle biopsy sample may be examined under amicroscope by, e.g., a pathologist. The report of a thyroid fine needlebiopsy followed by examination under a microscope will usually indicateone of the following findings:

1. The nodule is benign (noncancerous). This result is obtained in up to80% of biopsies. The risk of overlooking a cancer when the biopsy isbenign is generally less than 3 in 100 tests or 3%. This is even lowerwhen the biopsy is reviewed by an experienced pathologist at a majormedical center. Generally, benign thyroid nodules do not need to beremoved unless they are causing symptoms like choking or difficultyswallowing. Follow up ultrasound exams are important. Occasionally,another biopsy may be required in the future, especially if the nodulegrows over time.

2. The nodule is malignant (cancerous) or suspicious for malignancy. Amalignant result is obtained in about 5% of biopsies and is most oftendue to papillary cancer, which is the most common type of thyroidcancer. A malignant diagnosis has a >99% risk of cancer in the nodule. Asuspicious biopsy has a 50-75% risk of cancer in the nodule. Thesediagnoses require surgical removal of the thyroid after consultationwith the endocrinologist and surgeon.

3. The nodule is indeterminate. This is actually a group of severaldiagnoses that may occur in up to 30% of cases. An indeterminate findingmeans that even though an adequate number of cells was removed duringthe fine needle biopsy, examination with a microscope cannot reliablyclassify the result as benign or cancer. The biopsy may be indeterminatebecause the nodule is described as a Follicular Lesion. These nodulesare cancerous 20-30% of the time. However, under the current state ofthe art, the diagnosis can only be made by surgery. Because the oddsthat the nodule is not a cancer are much better by surgery (70-80%),only the side of the thyroid with the nodule is usually removed. If acancer is found, the remaining thyroid gland is usually removed as well.If the surgery confirms that no cancer is present, no additional surgeryto “complete” the thyroidectomy is necessary.

The biopsy may also be indeterminate because the cells from the nodulehave features that cannot be placed in one of the other diagnosticcategories. This diagnosis is called atypia, or a follicular lesion ofundetermined significance. Diagnoses in this category will containcancer rarely, so repeat evaluation with FNA or surgical biopsy toremove half of the thyroid containing the nodule is usually recommended.

4. The biopsy may also be non-diagnostic or inadequate. This resultindicates that not enough cells were obtained to make a diagnosis but isa common result if the nodule is a cyst. These nodules may requirereevaluation with second fine needle biopsy, or may need to be removedsurgically depending on the clinical judgment of the doctor.

Methods, compositions, kits, and systems provided herein providesignificant advantages over the visual examination of biopsies.

Method of Detection Methylation Status of a Thyroid Nodule DNA

In an aspect, provided herein is a method of detecting methylation orunmethylation of a thyroid nodule DNA of a subject. The method includes:(i) isolating a thyroid nodule DNA molecule from a thyroid nodule of thesubject thereby forming an isolated thyroid nodule DNA molecule, (ii)contacting the isolated thyroid nodule DNA molecule with a bisulfitesalt (such as sodium bisulfite) thereby forming a reacted thyroid noduleDNA molecule, (iii) detecting the presence or absence of uracil in thereacted thyroid nodule DNA molecule at a methylation site set forth inTable 1, thereby detecting methylation or unmethylation of the thyroidnodule DNA molecule of the subject. In embodiments, contacting theisolated thyroid nodule DNA with a bisulfite salt comprises adding asolution comprising the bisulfite salt to a solution comprising theisolated single stranded DNA.

In an aspect, provided herein is a method of detecting methylation orunmethylation of a thyroid nodule DNA molecule of a subject comprising(i) isolating a plurality of thyroid nodule DNA molecules from thethyroid nodule of the subject thereby forming a plurality of isolatedthyroid nodule DNA molecules, (ii) contacting the plurality of isolatedthyroid nodule DNA molecules with the bisulfite salt thereby forming aplurality of reacted thyroid nodule DNA molecules, (iii) detecting thelevel of reacted thyroid nodule DNA molecules in the plurality ofreacted thyroid nodule DNA molecules having a uracil at a methylationsite set forth in Table 1, thereby detecting the level of methylation orunmethylation in the plurality of thyroid nodule DNA molecules of thesubject.

In an aspect, provided herein is a method of detecting methylation orunmethylation of a thyroid nodule DNA molecule of a subject comprising(i) isolating a plurality of thyroid nodule DNA molecules from thethyroid nodule of the subject thereby forming a plurality of isolatedthyroid nodule DNA molecules, (ii) contacting the plurality of isolatedthyroid nodule DNA molecules with the bisulfite salt thereby forming aplurality of reacted thyroid nodule DNA molecules, (iii) detecting thepresence or absence of uracil in a reacted thyroid nodule DNA moleculeat a methylation site set forth in Table 1, thereby detectingmethylation or unmethylation of the thyroid nodule DNA molecule of thesubject.

In an aspect, provided herein is a method of detecting methylation orunmethylation of a thyroid nodule DNA of a subject. The method includes:(i) isolating a thyroid nodule DNA molecule from a thyroid nodule of thesubject thereby forming an isolated thyroid nodule DNA molecule, (ii)contacting the isolated thyroid nodule DNA molecule with a bisulfitesalt (such as sodium bisulfite) thereby forming a reacted thyroid noduleDNA molecule, (iii) amplifying the reacted thyroid nodule DNA moleculethereby forming a reacted thyroid nodule DNA amplicon molecule, (iv)detecting the presence or absence of thymidine in a reacted thyroidnodule DNA amplicon molecule at a methylation site set forth in Table 1,thereby detecting methylation or unmethylation of the thyroid nodule DNAmolecule of the subject. In embodiments, contacting the isolated thyroidnodule DNA with a bisulfite salt comprises adding a solution comprisingthe bisulfite salt to a solution comprising the isolated single strandedDNA.

In an aspect, provided herein is a method of detecting methylation orunmethylation of a thyroid nodule DNA molecule of a subject comprising(i) isolating a plurality of thyroid nodule DNA molecules from thethyroid nodule of the subject thereby forming a plurality of isolatedthyroid nodule DNA molecules, (ii) contacting the plurality of isolatedthyroid nodule DNA molecules with the bisulfite salt thereby forming aplurality of reacted thyroid nodule DNA molecules, (iii) amplifying theplurality of reacted thyroid nodule DNA molecules thereby forming aplurality of reacted thyroid nodule DNA amplicon molecules, (iv)detecting one or more thyroid nodule DNA amplicon molecules within theplurality of reacted thyroid nodule DNA amplicon molecules having athymidine at a methylation site set forth in Table 1, thereby detectingmethylation or unmethylation of the thyroid nodule DNA molecule of thesubject.

In embodiments, detecting one or more thyroid nodule DNA ampliconmolecules comprises detecting the level of one or more one or morethyroid nodule DNA amplicon molecules. In embodiments, detecting one ormore thyroid nodule DNA amplicon molecules comprises detecting the levelof reacted thyroid nodule DNA amplicon molecules in the plurality ofreacted thyroid nodule DNA amplicon molecules having a thymidine at amethylation site set forth in Table 1, thereby detecting the level ofmethylation or unmethylation in the plurality of thyroid nodule DNAmolecules of the subject.

In embodiments, detecting a level includes determining the number (e.g.quantitating) or molecules having, e.g., a thymidine or a uracil. Inembodiments, detecting a level includes detecting the portion orproportion of a population or plurality of molecules having, e.g., athymidine or a uracil.

In embodiments, the isolated thyroid nodule DNA sample is treated with abisulfite reagent, e.g., a bisulfite salt (i.e., a process called DNAbisulfite conversion). Non-limiting examples of bisulfite salts includesodium bisulfite, potassium bisulfite, ammonium bisulfite, magnesiumbisulfite, sodium metabisulfite, potassium metabisulfite, ammoniummetabisulfite and magnesium metabisulfite. Bisulfite salts such assodium bisulfite or ammonium bisulfite can convert cytosine to uraciland leave 5-methylcytosine (5-mC) the same. Thus after bisulfitetreatment methylated cytosine in the DNA remains the same and unmodifiedcytosines will be changed to uracil. The bisulfite treatment can beperformed by using the methods disclosed herein or in the art, and/orwith commercial kits such as the Bisulflash DNA Modification Kit(Epigentek) and Imprint DNA Modification Kit (Sigma). For achieving theoptimal bisulfite conversion, the bisulfite reaction should be carriedout in an appropriate concentration of bisulfite reagents, appropriatetemperature and appropriate reaction time period. A reagent such aspotassium chloride that reduces thermophilic DNA degradation could alsobe used in bisulfite treatment so that the DNA bisulfite process can bemuch shorter without interrupting a completed conversion of unmethylatedcytosine to uracil and without a significant thermodegradation of DNAresulted from depurination. In embodiments, a commercially availablebisulfite treatment kit is used. A non-limiting example of such a kit isEZ DNA Methylation-Gold™ Kit (Zymo Research, Irvine, CA, USA).

In embodiments, once DNA bisulfite conversion is complete, DNA iscaptured, desulphonated and washed. In embodiments, thebisulfite-treated DNA can be captured by, e.g., a solid matrix selectedfrom silica salt, silica dioxide, silica polymers, magnetic beads, glassfiber, celite diatoms and nitrocellulose in the presence of highconcentrations of chaotropic or non-chaotropic salts. In embodiments,the bisulfite-treated DNA is further desulphonated with an alkalizedsolution, preferably sodium hydroxide at concentrations from 10 mM to300 mM. In embodiments, the DNA is then eluted and collected into acapped microcentrifuge tube. Non-limiting examples of elution solutionsinclude DEPC-treated water and TE buffer (10 mM Tris-HCL, pH 8.0, and 1mM EDTA).

In embodiments, the reacted thyroid nodule DNA resulting from bisulfitetreatment is amplified. In embodiments, detecting the presence orabsence of uracil in reacted thyroid nodule DNA molecule at amethylation site comprises amplifying the reacted thyroid nodule DNAmolecule thereby forming a reacted thyroid nodule DNA amplicon molecule,and detecting the presence or absence of thymidine in a reacted thyroidnodule DNA amplicon molecule at the methylation site. In embodiments, apolymerase chain reaction (PCR) method is used for amplifying thereacted thyroid nodule DNA. PCR methods are known to those of ordinaryskill in the art. In general, the PCR reactions can be set up by addingsample, dNTPs, and appropriate polymerase such as Taq polymerase,primers, and a buffer.

In embodiments, the method of detecting methylation or unmethylation ofa thyroid nodule DNA of a subject, includes detecting methylation orunmethylation at a plurality of methylation sites set forth in Table 1.In embodiments, the plurality of methylation sites comprises at leastabout 2, 3, 4, 5, 10, 25, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300,350, 400, 450, 500, or 550, or 5-550 methylation sites. In embodiments,the plurality of methylation sites comprises less than about 550, 500,450, 400, 350, 300, 250, 200, 150, 100, 90, 85, 80, 75, 50, 25, or 10methylation sites. In embodiments, the plurality of methylation sites isabout 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 50,75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 550, or5-550 methylation sites. In embodiments, the plurality of methylationsites includes two or more methylation sites set forth in Table 1 and noother methylation sites.

In embodiments, the method includes detecting methylation orunmethylation of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 50, 100, 200,300, 400, or 500 of the following sites: Chromosome 1 (Chr1) position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chromosome 2 (Chr2)position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2position 74454110, Chr2 position 122014529, Chr2 position 128158884,Chr2 position 128158910, Chr2 position 203114171, Chr2 position218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2position 238341542, Chr2 position 238341546, Chr2 position 238774763,Chromosome 3 (Chr3) position 13323642, Chr3 position 14180153, Chr3position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3position 73599302, Chr3 position 195636893, Chr3 position 197093846,Chromosome 4 (Chr4) position 3743223, Chr4 position 5755716, Chr4position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chromosome 5 (Chr5) position 1118280, Chr5 position 34564389, Chr5position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5position 137802650, Chr5 position 139051189, Chr5 position 167838221,Chr5 position 177541401, Chr5 position 180018672, Chr5 position180101026, Chromosome 6 (Chr6) position 3394325, Chr6 position 3887581,Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617,Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516,Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279,Chromosome 7 (Chr7) position 989235, Chr7 position 2673543, Chr7position 73508602, Chr7 position 105079565, Chr7 position 105079631,Chr7 position 151425103, Chr7 position 151425104, Chromosome 8 (Chr8)position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8position 22548483, Chr8 position 133570537, Chr8 position 141320393,Chr8 position 141320410, Chromosome 9 (Chr9) position 6566568, Chr9position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9position 126126741, Chr9 position 132083428, Chr9 position 136077410,Chr9 position 139655018, Chr9 position 140205985, Chr9 position140205985, Chr9 position 140205997, Chromosome 10 (Chr10) position3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10position 87984905, Chr10 position 94838789, Chr10 position 102131187,Chr10 position 104196489, Chr10 position 111766879, Chr10 position112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10position 116391763, Chr10 position 120011530, Chr10 position 126172714,Chr10 position 126172747, Chromosome 11 (Chr11) position 556355, Chr11position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11position 12188995, Chr11 position 36057726, Chr11 position 48070143,Chr11 position 48070163, Chr11 position 48070166, Chr11 position48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11position 65297089, Chr11 position 66104481, Chr11 position 66104485,Chr11 position 66104578, Chr11 position 68608767, Chr11 position70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11position 115530032, Chr11 position 117950310, Chr11 position 117950329,Chr11 position 117950361, Chr11 position 117950362, Chr11 position119293593, Chromosome 12 (Chr12) position 679803, Chr12 position26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12position 45610701, Chr12 position 45610702, Chr12 position 45610706,Chr12 position 50286016, Chr12 position 52243258, Chr12 position52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12position 54145825, Chr12 position 56115043, Chr12 position 66262229,Chr12 position 66262230, Chr12 position 66262233, Chr12 position66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12position 123435962, Chr12 position 123436011, Chr12 position 123436065,Chr12 position 123540893, Chromosome 13 (Chr13) position 20735797, Chr13position 23500419, Chr13 position 46771519, Chr13 position 46771520,Chr13 position 53313426, Chr13 position 113807393, Chromosome 14 (Chr14)position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chromosome 15 (Chr15) position 41068807, Chr15position 61152225, Chr15 position 61152253, Chr15 position 61152313,Chr15 position 65186440, Chr15 position 68851629, Chr15 position70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15position 77984014, Chr15 position 77989064, Chr15 position 83952081,Chr15 position 85402496, Chr15 position 85402497, Chr15 position99417337, Chromosome 16 (Chr16) position 1231873, Chr16 position1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16position 31009590, Chr16 position 57793674, Chr16 position 57793715,Chr16 position 57793727, Chr16 position 70771056, Chr16 position70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16position 78540378, Chr16 position 79333435, Chr16 position 84262419,Chr16 position 88701114, Chr16 position 89988308, Chr16 position89988644, Chromosome 17 (Chr17) position 1509928, Chr17 position1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17position 16924561, Chr17 position 16924562, Chr17 position 16924594,Chr17 position 17717918, Chr17 position 17718591, Chr17 position18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17position 40826257, Chr17 position 43037426, Chr17 position 43200096,Chr17 position 43200239, Chr17 position 43510142, Chr17 position47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17position 48764165, Chr17 position 55701962, Chr17 position 73584599,Chr17 position 73993165, Chr17 position 75827716, Chr17 position76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17position 80696474, Chromosome 18 (Chr18) position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chromosome 19 (Chr19)position 677895, Chr19 position 884044, Chr19 position 884059, Chr19position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19position 10254578, Chr19 position 10463956, Chr19 position 10464137,Chr19 position 13203671, Chr19 position 13266925, Chr19 position13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19position 14248494, Chr19 position 15375465, Chr19 position 17218912,Chr19 position 17346702, Chr19 position 17346702, Chr19 position18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19position 18415877, Chr19 position 18415890, Chr19 position 30606642,Chr19 position 35531842, Chr19 position 44303112, Chr19 position47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19position 47778298, Chromosome 20 (Chr20) position 34206950, Chr20position 36771969, Chr20 position 48993661, Chr20 position 58406398,Chr20 position 61976049, Chr20 position 61976073, Chr20 position62588571, Chr20 position 62588579, Chromosome 22 (Chr22) position19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22position 36973375, Chr22 position 37447953, Chr22 position 37914998,Chr22 position 38307317, Chr22 position 39662794, and Chr22 position45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 1 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 2 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 3 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 4 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 5 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 6 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 7 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 8 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 9 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 10 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 50 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 100 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 200 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 300 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Ch19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 400 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, the method includes detecting methylation orunmethylation of at least 500 of the following sites: Chr1 position2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1position 110074681, Chr1 position 110074685, Chr1 position 150949856,Chr1 position 150949857, Chr1 position 153540282, Chr1 position155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1position 157611881, Chr1 position 182205324, Chr1 position 204118999,Chr1 position 206741875, Chr1 position 206741989, Chr1 position212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2position 122014529, Chr2 position 128158884, Chr2 position 128158910,Chr2 position 203114171, Chr2 position 218221671, Chr2 position219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2position 238341546, Chr2 position 238774763, Chr3 position 13323642,Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207,Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317,Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893,Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716,Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729,Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289,Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907,Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650,Chr5 position 139051189, Chr5 position 167838221, Chr5 position177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7position 105079631, Chr7 position 151425103, Chr7 position 151425104,Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399,Chr8 position 22548483, Chr8 position 133570537, Chr8 position141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9position 139655018, Chr9 position 140205985, Chr9 position 140205985,Chr9 position 140205997, Chr10 position 3929071, Chr10 position30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10position 94838789, Chr10 position 102131187, Chr10 position 104196489,Chr10 position 111766879, Chr10 position 112258886, Chr10 position112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10position 120011530, Chr10 position 126172714, Chr10 position 126172747,Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937,Chr11 position 12188948, Chr11 position 12188995, Chr11 position36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11position 48070166, Chr11 position 48070174, Chr11 position 65158294,Chr11 position 65158342, Chr11 position 65297089, Chr11 position66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11position 68608767, Chr11 position 70236292, Chr11 position 70236320,Chr11 position 70236331, Chr11 position 115530032, Chr11 position117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11position 117950362, Chr11 position 119293593, Chr12 position 679803,Chr12 position 26039132, Chr12 position 31004558, Chr12 position45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12position 45610706, Chr12 position 50286016, Chr12 position 52243258,Chr12 position 52243286, Chr12 position 54145732, Chr12 position54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12position 66262229, Chr12 position 66262230, Chr12 position 66262233,Chr12 position 66262234, Chr12 position 77266621, Chr12 position117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12position 123436065, Chr12 position 123540893, Chr13 position 20735797,Chr13 position 23500419, Chr13 position 46771519, Chr13 position46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14position 38599118, Chr14 position 69170010, Chr14 position 75701632,Chr14 position 75701643, Chr14 position 90850454, Chr14 position97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14position 104209000, Chr14 position 104209068, Chr14 position 104354645,Chr14 position 104360487, Chr15 position 41068807, Chr15 position61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15position 65186440, Chr15 position 68851629, Chr15 position 70667596,Chr15 position 70767206, Chr15 position 75251486, Chr15 position77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15position 85402496, Chr15 position 85402497, Chr15 position 99417337,Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231,Chr16 position 23135832, Chr16 position 29616265, Chr16 position31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16position 57793674, Chr16 position 57793715, Chr16 position 57793727,Chr16 position 70771056, Chr16 position 70771079, Chr16 position70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16position 79333435, Chr16 position 84262419, Chr16 position 88701114,Chr16 position 89988308, Chr16 position 89988644, Chr17 position1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17position 16924594, Chr17 position 17717918, Chr17 position 17718591,Chr17 position 18139506, Chr17 position 35278031, Chr17 position39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17position 43200096, Chr17 position 43200239, Chr17 position 43510142,Chr17 position 47987828, Chr17 position 48178379, Chr17 position48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17position 73584599, Chr17 position 73993165, Chr17 position 75827716,Chr17 position 76882243, Chr17 position 78765910, Chr17 position79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18position 21440760, Chr18 position 45555437, Chr18 position 45555438,Chr18 position 46547891, Chr18 position 55888885, Chr18 position56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19position 884044, Chr19 position 884059, Chr19 position 884105, Chr19position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19position 8428573, Chr19 position 10254577, Chr19 position 10254578,Chr19 position 10463956, Chr19 position 10464137, Chr19 position13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19position 13266970, Chr19 position 13842142, Chr19 position 14248494,Chr19 position 15375465, Chr19 position 17218912, Chr19 position17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19position 18157221, Chr19 position 18157258, Chr19 position 18415877,Chr19 position 18415890, Chr19 position 30606642, Chr19 position35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19position 47316268, Chr19 position 47778278, Chr19 position 47778298,Chr20 position 34206950, Chr20 position 36771969, Chr20 position48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20position 61976073, Chr20 position 62588571, Chr20 position 62588579,Chr22 position 19738127, Chr22 position 35965176, Chr22 position36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22position 37914998, Chr22 position 38307317, Chr22 position 39662794, andChr22 position 45622980.

In embodiments, a method provided herein is practiced for a subject morethan once over time. In embodiments, methylation or unmethylation ofthyroid nodule DNA from a subject is assessed using a method providedherein at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times. Inembodiments, the method is repeated at least once every 4, 6, 8, 12 or18 months, or at least once every 2, 3, 4, or 5 more years.

In embodiments, the method includes: (i) isolating DNA from multiplecells of a thyroid nodule of the subject thereby forming a plurality ofisolated thyroid nodule DNA molecules, (ii) contacting the plurality ofisolated thyroid nodule DNA molecules with a bisulfite salt therebyforming a plurality of reacted thyroid nodule DNA molecules, (iii)detecting the proportion of DNA molecules in the plurality of reactedthyroid nodule DNA molecules having a uracil at a methylation site setforth in Table 1, thereby detecting methylation or unmethylation of saidthyroid nodule DNA of the subject.

The methylation of a CpG site of interest may vary between individualcells (and even between chromosome pairs of individual cells) in abiological sample. When DNA is obtained from a biological sample andtreated with a bisulfite salt to convert unmethylated cytosines touracils, the bisulfite-treated DNA will typically contain (i) aproportion of DNA molecules with a cytosine at the site of interest(indicating that the site was methylated); and (ii) a proportion of DNAmolecules with a uracil at the site of interest (indicating that thesite was unmethylated). Since a uracil at a site of interest inbisulfite-treated DNA indicates that the site was unmethylated in theuntreated DNA, a thymidine at the corresponding site in an amplicon ofthe bisulfite-treated DNA (e.g., an amplicon obtained by PCR) alsoindicates that the site was unmethylated in the untreated DNA.

In embodiments, the level of methylation at a site of interest is theproportion of bisulfite-treated DNA molecules having a cytosine ratherthan a uracil at that site of interest. In embodiments, the level ofmethylation at a site of interest is the proportion of amplicons ofbisulfite-treated DNA molecules having a cytosine rather than athymidine at that site of interest.

In embodiments, the level of unmethylation at a site of interest is theproportion of bisulfite-treated DNA molecules having a uracil ratherthan a cytosine at that site of interest. In embodiments, the level ofunmethylation at a site of interest is the proportion of amplicons ofbisulfite-treated DNA molecules having a thymidine rather than acytosine at that site of interest. In Table 1, an indicated level ofuracil is the proportion of bisulfite-treated DNA molecules having auracil rather than a cytosine at the specified methylation site. Thesame levels listed in Table 1 also apply to the thymidine levels at asite of interest in an amplicon, i.e., the proportion of amplicons(derived from the PCR amplification of bisulfite-treated DNA molecules)having a thymidine rather than a cytosine at the specified methylationsite.

The level of DNA methylation at a site of interest (e.g., a methylationsite listed in Table 1) may be determined using sequencing technology.Sequencing technology can reveal nucleotide sequence variations in aplurality of DNA molecules at a single nucleotide base resolution. Forexample, the proportions of corresponding DNA molecules having a uracil,a thymidine, and/or a cytosine at a site may be determined. Anon-limiting example of a sequencing-based method for determining themethylation level at a site of interest is described in Masser et al.(2015) Targeted DNA Methylation Analysis by Next-generation Sequencing,J Vis Exp. (96): 52488, the entire content of which is incorporatedherein by reference.

The chromosomal positions listed in Tables 1-4 relate to the humangenome that is publically accessible in the University of CaliforniaSanta Cruz (UCSC) genome browser database under accession number HG19,the entire content of which is incorporated herein by reference in itsentirety. Non-limiting information regarding the UCSC Genome Browser isprovided in Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, ZahlerAM, Haussler D. The human genome browser at UCSC. Genome Res. 2002Jun;12(6):996-1006, the entire content of which is incorporated hereinby reference. Each methylation site of interest listed in Table 1 may belocated in other human genomes (e.g., within the genome of a specificsubject or group of subjects) by replacing every U and R in thecorresponding sequence with a C and then searching for the location ofthe X within a reference genome by aligning the sequence against thereference genome. For example, the methylation site of interest “X” inSEQ ID NO: 1 may be located within a genome by replacing each U and R inSEQ ID NO: 1 with a C (to obtain the pre-bisulfite-modified sequencehaving an X at the site of interest) and then aligning the sequenceagainst the genome using a BLAST algorithm. Also expressly provided,disclosed, and incorporated herein is the non-bisulfite-modifiedsequence corresponding to each of SEQ ID NOS: 1-550. Thenon-bisulfite-modified sequence corresponding to each of SEQ ID NOS:1-550 is each respective sequence in which each U and R is replaced witha C, where X is the methylation site of interest. For example, thenon-bisulfite-modified sequence corresponding to SEQ ID NO: 1 providedherein is a modified version of SEQ ID NO: 1 in which each U and R inSEQ ID NO: 1 is replaced with a C, where X is the methylation site ofinterest; the non-bisulfite-modified sequence corresponding to SEQ IDNO:2 provided herein is a modified version of SEQ ID NO:2 in which eachU and R in SEQ ID NO:2 is replaced with a C, where X is the methylationsite of interest; the non-bisulfite-modified sequence corresponding toSEQ ID NO:3 provided herein is a modified version of SEQ ID NO:3 inwhich each U and R in SEQ ID NO:3 is replaced with a C, where X is themethylation site of interest, and so on.

TABLE 1 Chromosome (chr) Chr Position Uracil level in reacted thyroidnodule DNA from cancer tissues is above indicated level* Uracil level inreacted thyroid nodule DNA from benign tissues is above indicated level*Uracil level in reacted thyroid nodule DNA from benign tissues is belowindicated level* SEQ ID NO: Forward Strand SEQ ID NO: Reverse Strandchr1 2996653 N/A 88.84 N/A 1 2 chr1 11979164 89.29 N/A N/A 3 4 chr112655938 N/A N/A 69.23 5 6 chr1 16450525 70.00 N/A N/A 7 8 chr1 1645054272.00 N/A N/A 7 8 chr1 16450545 73.33 N/A N/A 7 8 chr1 16469987 80.00N/A N/A 9 10 chr1 17494491 86.00 N/A N/A 11 12 chr1 25473203 88.89 N/AN/A 13 14 chr1 27640460 N/A 80.56 N/A 15 16 chr1 29565080 N/A N/A 60.0017 18 chr1 38493013 86.36 N/A N/A 19 20 chr1 38493030 79.17 N/A N/A 1920 chr1 38493074 80.95 N/A N/A 19 20 chr1 46713777 N/A N/A 73.33 21 22chr1 46914121 N/A N/A 60.00 23 24 chr1 46955744 N/A N/A 77.78 25 26 chr155008344 N/A N/A 60.00 27 28 chr1 109816092 80.77 N/A N/A 29 30 chr1109816111 80.77 N/A N/A 29 30 chr1 110074669 75.00 N/A N/A 31 32 chr1110074681 71.43 N/A N/A 31 32 chr1 110074685 63.16 N/A N/A 31 32 chr1150949856 89.29 N/A N/A 33 34 chr1 150949857 88.46 N/A N/A 33 34 chr1153540282 78.26 N/A N/A 35 36 chr1 155162704 84.21 N/A N/A 37 38 chr1155162714 88.64 N/A N/A 37 38 chr1 156676611 N/A N/A 84.62 39 40 chr1157611881 83.05 N/A N/A 41 42 chr1 182205324 77.50 N/A N/A 43 44 chr1204118999 59.09 N/A N/A 45 46 chr1 206741875 83.33 N/A N/A 47 48 chr1206741989 66.67 N/A N/A 49 50 chr1 212587673 N/A N/A 80.00 51 52 chr1212841198 85.29 N/A N/A 53 54 chr1 223403952 79.17 N/A N/A 55 56 chr1233430972 N/A N/A 86.67 57 58 chr1 234342767 76.67 N/A N/A 59 60 chr103929071 88.68 N/A N/A 61 62 chr10 30047012 86.84 N/A N/A 63 64 chr1079702989 83.33 N/A N/A 65 66 chr10 87984905 86.36 N/A N/A 67 68 chr1094838789 63.33 N/A N/A 69 70 chr10 102131187 90.00 N/A N/A 71 72 chr10104196489 75.00 N/A N/A 73 74 chr10 111766879 89.47 N/A N/A 75 76 chr10112258886 81.82 N/A N/A 77 78 chr10 112258984 83.33 N/A N/A 79 80 chr10112259015 82.61 N/A N/A 79 80 chr10 116391763 N/A N/A 75.00 81 82 chr10120011530 79.55 N/A N/A 83 84 chr10 126172714 N/A 80.00 N/A 85 86 chr10126172747 N/A 84.62 N/A 85 86 chr11 556355 N/A N/A 75.00 87 88 chr11821282 89.13 N/A N/A 89 90 chr11 12188937 83.33 N/A N/A 91 92 chr1112188948 77.78 N/A N/A 91 92 chr11 12188995 78.57 N/A N/A 93 94 chr1136057726 N/A 79.63 N/A 95 96 chr11 48070143 N/A 84.38 N/A 97 98 chr1148070163 N/A 87.50 N/A 97 98 chr11 48070166 N/A 84.38 N/A 97 98 chr1148070174 N/A 84.48 N/A 97 98 chr11 65158294 78.00 N/A N/A 99 100 chr1165158342 85.00 N/A N/A 99 100 chr11 65297089 75.00 N/A N/A 101 102 chr1166104481 81.58 N/A N/A 103 104 chr11 66104485 83.33 N/A N/A 103 104chr11 66104578 81.82 N/A N/A 105 106 chr11 68608767 N/A N/A 73.33 107108 chr11 70236292 89.29 N/A N/A 109 110 chr11 70236320 85.71 N/A N/A109 110 chr11 70236331 70.83 N/A N/A 109 110 chr11 115530032 N/A N/A79.49 111 112 chr11 117950310 79.55 N/A N/A 113 114 chr11 11795032979.55 N/A N/A 113 114 chr11 117950361 80.00 N/A N/A 115 116 chr11117950362 81.82 N/A N/A 115 116 chr11 119293593 N/A N/A 60.00 117 118chr12 679803 86.84 N/A N/A 119 120 chr12 26039132 73.91 N/A N/A 121 122chr12 31004558 N/A N/A 81.82 123 124 chr12 45610695 N/A N/A 83.33 125126 chr12 45610701 N/A N/A 86.67 125 126 chr12 45610702 N/A N/A 89.47125 126 chr12 45610706 N/A N/A 80.00 125 126 chr12 50286016 82.14 N/AN/A 127 128 chr12 52243258 82.00 N/A N/A 129 130 chr12 52243286 82.50N/A N/A 129 130 chr12 54145732 N/A N/A 82.35 131 132 chr12 54145741 N/AN/A 76.47 131 132 chr12 54145825 N/A N/A 70.59 131 132 chr12 5611504389.29 N/A N/A 133 134 chr12 66262229 72.22 N/A N/A 135 136 chr1266262230 71.74 N/A N/A 135 136 chr12 66262233 68.27 N/A N/A 135 136chr12 66262234 71.74 N/A N/A 135 136 chr12 77266621 N/A 73.53 N/A 137138 chr12 117580102 84.62 N/A N/A 139 140 chr12 123435962 63.89 N/A N/A141 142 chr12 123436011 71.88 N/A N/A 143 144 chr12 123436065 69.44 N/AN/A 143 144 chr12 123540893 77.27 N/A N/A 145 146 chr13 20735797 N/A N/A82.35 147 148 chr13 23500419 N/A N/A 68.42 149 150 chr13 46771519 67.65N/A N/A 151 152 chr13 46771520 73.91 N/A N/A 151 152 chr13 53313426 N/AN/A 60.00 153 154 chr13 113807393 N/A N/A 27.27 155 156 chr14 3859911865.91 N/A N/A 157 158 chr14 69170010 86.36 N/A N/A 159 160 chr1475701632 68.42 N/A N/A 161 162 chr14 75701643 68.75 N/A N/A 161 162chr14 90850454 N/A N/A 54.55 163 164 chr14 97524282 N/A 88.89 N/A 165166 chr14 103541602 N/A N/A 52.00 167 168 chr14 103768055 76.09 N/A N/A169 170 chr14 104209000 N/A 80.77 N/A 171 172 chr14 104209068 N/A 83.33N/A 171 172 chr14 104354645 72.92 N/A N/A 173 174 chr14 104360487 83.33N/A N/A 175 176 chr15 41068807 69.12 N/A N/A 177 178 chr15 6115222583.33 N/A N/A 179 180 chr15 61152253 86.67 N/A N/A 181 182 chr1561152313 86.67 N/A N/A 183 184 chr15 65186440 N/A N/A 55.56 185 186chr15 68851629 N/A N/A 63.64 187 188 chr15 70667596 83.33 N/A N/A 189190 chr15 70767206 90.00 N/A N/A 191 192 chr15 75251486 N/A N/A 60.00193 194 chr15 77984014 N/A 88.89 N/A 195 196 chr15 77989064 73.53 N/AN/A 197 198 chr15 83952081 N/A N/A 72.73 199 200 chr15 85402496 82.10N/A N/A 201 202 chr15 85402497 79.49 N/A N/A 201 202 chr15 9941733788.89 N/A N/A 203 204 chr16 1231873 86.36 N/A N/A 205 206 chr16 1458639N/A N/A 75.00 207 208 chr16 3023231 N/A 84.00 N/A 209 210 chr16 2313583287.50 N/A N/A 211 212 chr16 29616265 85.71 N/A N/A 213 214 chr1631009547 84.00 N/A N/A 215 216 chr16 31009548 85.00 N/A N/A 215 216chr16 31009590 85.00 N/A N/A 215 216 chr16 57793674 80.95 N/A N/A 217218 chr16 57793715 85.71 N/A N/A 217 218 chr16 57793727 80.95 N/A N/A217 218 chr16 70771056 68.75 N/A N/A 219 220 chr16 70771079 63.33 N/AN/A 219 220 chr16 70771141 65.79 N/A N/A 219 220 chr16 77332010 72.58N/A N/A 221 222 chr16 78540378 75.76 N/A N/A 223 224 chr16 79333435 N/A89.61 N/A 225 226 chr16 84262419 87.23 N/A N/A 227 228 chr16 88701114N/A N/A 66.67 229 230 chr16 89988308 N/A N/A 83.33 231 232 chr1689988644 N/A N/A 47.37 233 234 chr17 1509928 N/A 88.46 N/A 235 236 chr171509945 N/A 88.46 N/A 235 236 chr17 1509952 N/A 83.93 N/A 235 236 chr171509953 N/A 85.00 N/A 235 236 chr17 7644013 N/A 85.42 N/A 237 238 chr1716323460 85.00 N/A N/A 239 240 chr17 16323473 84.21 N/A N/A 239 240chr17 16924561 80.36 N/A N/A 241 242 chr17 16924562 75.71 N/A N/A 241242 chr17 16924594 75.71 N/A N/A 241 242 chr17 17717918 72.73 N/A N/A243 244 chr17 17718591 84.38 N/A N/A 245 246 chr17 18139506 82.81 N/AN/A 247 248 chr17 35278031 N/A N/A 28.42 249 250 chr17 39677570 71.88N/A N/A 251 252 chr17 40826257 N/A N/A 23.81 253 254 chr17 43037426 N/AN/A 33.33 255 256 chr17 43200096 77.78 N/A N/A 257 258 chr17 4320023985.00 N/A N/A 259 260 chr17 43510142 N/A N/A 81.82 261 262 chr1747987828 N/A N/A 69.23 263 264 chr17 48178379 83.33 N/A N/A 265 266chr17 48596391 N/A 88.64 N/A 267 268 chr17 48764165 88.89 N/A N/A 269270 chr17 55701962 68.75 N/A N/A 271 272 chr17 73584599 N/A N/A 60.00273 274 chr17 73993165 90.00 N/A N/A 275 276 chr17 75827716 78.57 N/AN/A 277 278 chr17 76882243 61.54 N/A N/A 279 280 chr17 78765910 88.71N/A N/A 281 282 chr17 79544478 83.15 N/A N/A 283 284 chr17 8069647460.00 N/A N/A 285 286 chr18 19751759 N/A N/A 33.33 287 288 chr1821440760 67.86 N/A N/A 289 290 chr18 45555437 66.18 N/A N/A 291 292chr18 45555438 73.68 N/A N/A 291 292 chr18 46547891 76.09 N/A N/A 293294 chr18 55888885 75.47 N/A N/A 295 296 chr18 56452096 90.00 N/A N/A297 298 chr18 56452476 81.82 N/A N/A 299 300 chr18 56887181 N/A N/A60.00 301 302 chr18 76002973 81.58 N/A N/A 303 304 chr18 77331090 81.03N/A N/A 305 306 chr19 677895 85.29 N/A N/A 307 308 chr19 884044 76.92N/A N/A 309 310 chr19 884059 76.92 N/A N/A 309 310 chr19 884105 84.62N/A N/A 311 312 chr19 884115 84.62 N/A N/A 311 312 chr19 1136511 86.96N/A N/A 313 314 chr19 1177605 73.68 N/A N/A 315 316 chr19 1177612 72.73N/A N/A 315 316 chr19 1177640 81.82 N/A N/A 315 316 chr19 1860601 88.46N/A N/A 317 318 chr19 1860607 82.81 N/A N/A 317 318 chr19 2503954 90.00N/A N/A 319 320 chr19 3434917 N/A N/A 40.00 321 322 chr19 3434921 N/AN/A 42.86 321 322 chr19 3434930 N/A N/A 57.14 321 322 chr19 3434939 N/AN/A 71.43 321 322 chr19 3434952 N/A N/A 71.43 321 322 chr19 3434954 N/AN/A 60.00 321 322 chr19 3434962 N/A N/A 71.43 321 322 chr19 3434964 N/AN/A 71.43 321 322 chr19 3434979 N/A N/A 66.67 321 322 chr19 3434985 N/AN/A 55.56 321 322 chr19 4052713 85.56 N/A N/A 323 324 chr19 405271485.14 N/A N/A 323 324 chr19 4052749 84.62 N/A N/A 323 324 chr19 437459182.14 N/A N/A 325 326 chr19 5013982 N/A 83.33 N/A 327 328 chr19 504883677.27 N/A N/A 329 330 chr19 5048867 70.59 N/A N/A 329 330 chr19 504887773.53 N/A N/A 329 330 chr19 8367279 75.00 N/A N/A 331 332 chr19 8428573N/A N/A 75.00 333 334 chr19 10254577 76.25 N/A N/A 335 336 chr1910254578 79.17 N/A N/A 335 336 chr19 10463956 N/A 86.73 N/A 337 338chr19 10464137 N/A 89.29 N/A 339 340 chr19 13203671 75.86 N/A N/A 341342 chr19 13266925 N/A N/A 66.67 343 344 chr19 13266934 N/A N/A 66.67343 344 chr19 13266970 N/A N/A 63.64 343 344 chr19 13842142 N/A N/A76.47 345 346 chr19 14248494 N/A N/A 73.91 347 348 chr19 15375465 72.22N/A N/A 349 350 chr19 17218912 81.25 N/A N/A 351 352 chr19 17346702 N/AN/A 85.71 353 354 chr19 17346702 N/A N/A 78.95 353 354 chr19 1815716188.24 N/A N/A 355 356 chr19 18157221 86.76 N/A N/A 357 358 chr1918157258 65.22 N/A N/A 359 360 chr19 18415877 N/A N/A 47.83 361 362chr19 18415890 N/A N/A 47.83 361 362 chr19 30606642 80.56 N/A N/A 363364 chr19 35531842 N/A N/A 83.33 365 366 chr19 44303112 N/A N/A 77.78367 368 chr19 47173037 N/A 88.64 N/A 369 370 chr19 47316268 76.67 N/AN/A 371 372 chr19 47778278 N/A N/A 66.67 373 374 chr19 47778298 N/A N/A83.33 373 374 chr2 3454277 N/A 84.78 N/A 375 376 chr2 8793724 N/A 78.57N/A 377 378 chr2 20412441 85.71 N/A N/A 379 380 chr2 42329402 N/A N/A78.95 381 382 chr2 42329494 N/A N/A 60.00 381 382 chr2 55289272 N/A75.00 N/A 383 384 chr2 65064865 64.71 N/A N/A 385 386 chr2 7082364179.03 N/A N/A 387 388 chr2 73143689 N/A N/A 77.78 389 390 chr2 7445411070.00 N/A N/A 391 392 chr2 122014529 N/A 86.36 N/A 393 394 chr2128158884 85.00 N/A N/A 395 396 chr2 128158910 77.50 N/A N/A 395 396chr2 203114171 79.63 N/A N/A 397 398 chr2 218221671 N/A 85.19 N/A 399400 chr2 219745335 N/A N/A 81.82 401 402 chr2 238341465 86.36 N/A N/A403 404 chr2 238341542 90.00 N/A N/A 405 406 chr2 238341546 87.50 N/AN/A 405 406 chr2 238774763 67.57 N/A N/A 407 408 chr20 31126186 87.50N/A N/A 409 410 chr20 31126189 84.21 N/A N/A 409 410 chr20 34206950 N/AN/A 76.47 411 412 chr20 36771969 79.31 N/A N/A 413 414 chr20 4899366180.00 N/A N/A 415 416 chr20 58406398 89.66 N/A N/A 417 418 chr2061976049 87.93 N/A N/A 419 420 chr20 61976073 89.66 N/A N/A 419 420chr20 62588571 N/A N/A 50.00 421 422 chr20 62588579 N/A N/A 38.46 421422 chr22 19738127 70.59 N/A N/A 423 424 chr22 35965176 76.32 N/A N/A425 426 chr22 36549809 83.33 N/A N/A 427 428 chr22 36973375 80.43 N/AN/A 429 430 chr22 37447953 N/A N/A 73.33 431 432 chr22 37914998 N/A N/A69.23 433 434 chr22 38307317 N/A 89.66 N/A 435 436 chr22 39662794 84.62N/A N/A 437 438 chr22 45622980 85.00 N/A N/A 439 440 chr3 13323642 N/AN/A 72.73 441 442 chr3 14180153 57.89 N/A N/A 443 444 chr3 45209073 N/AN/A 60.00 445 446 chr3 45209207 N/A N/A 83.33 447 448 chr3 5252510079.41 N/A N/A 449 450 chr3 62589658 87.50 N/A N/A 451 452 chr3 6538831771.43 N/A N/A 453 454 chr3 65388388 79.31 N/A N/A 455 456 chr3 7359930285.11 N/A N/A 457 458 chr3 195636893 N/A N/A 84.62 459 460 chr3197093846 80.00 N/A N/A 461 462 chr4 3743223 68.18 N/A N/A 463 464 chr45755716 85.48 N/A N/A 465 466 chr4 5755717 80.00 N/A N/A 465 466 chr45755728 82.26 N/A N/A 465 466 chr4 5755729 79.17 N/A N/A 465 466 chr45755734 79.17 N/A N/A 465 466 chr4 8372861 N/A 85.71 N/A 467 468 chr457548289 80.23 N/A N/A 469 470 chr5 1118280 73.08 N/A N/A 471 472 chr534564389 89.29 N/A N/A 473 474 chr5 73871907 89.47 N/A N/A 475 476 chr578013596 70.00 N/A N/A 477 478 chr5 78013643 80.00 N/A N/A 479 480 chr5137802650 72.73 N/A N/A 481 482 chr5 139051189 84.09 N/A N/A 483 484chr5 167838221 68.18 N/A N/A 485 486 chr5 177541401 N/A N/A 69.23 487488 chr5 180018672 N/A N/A 72.73 489 490 chr5 180101026 N/A N/A 64.71491 492 chr6 3394325 N/A 87.84 N/A 493 494 chr6 3887581 N/A 85.71 N/A495 496 chr6 7236568 84.43 N/A N/A 497 498 chr6 7728692 N/A N/A 73.33499 500 chr6 34203617 N/A N/A 45.45 501 502 chr6 37751320 N/A N/A 78.57503 504 chr6 41410682 N/A N/A 77.78 505 506 chr6 41438516 N/A N/A 39.13507 508 chr6 41438575 89.66 N/A N/A 507 508 chr6 43464150 75.76 N/A N/A509 510 chr6 158734279 N/A 86.84 N/A 511 512 chr7 989235 76.67 N/A N/A513 514 chr7 2673543 82.14 N/A N/A 515 516 chr7 73508602 N/A N/A 85.71517 518 chr7 105079565 78.75 N/A N/A 519 520 chr7 105079631 71.25 N/AN/A 519 520 chr7 151425103 86.96 N/A N/A 521 522 chr7 151425104 76.19N/A N/A 521 522 chr8 11764017 80.77 N/A N/A 523 524 chr8 21647308 N/AN/A 71.43 525 526 chr8 22548399 N/A 88.16 N/A 527 528 chr8 22548483 N/A87.50 N/A 527 528 chr8 133570537 N/A 80.00 N/A 529 530 chr8 14132039375.00 N/A N/A 531 532 chr8 141320410 85.00 N/A N/A 531 532 chr9 656656886.84 N/A N/A 533 534 chr9 16197862 N/A 86.36 N/A 535 536 chr9 34591313N/A N/A 80.00 537 538 chr9 98225096 N/A N/A 22.22 539 540 chr9 12612674186.11 N/A N/A 541 542 chr9 132083428 N/A N/A 70.59 543 544 chr9136077410 73.91 N/A N/A 545 546 chr9 139655018 83.33 N/A N/A 547 548chr9 140205985 75.00 N/A N/A 549 550 chr9 140205985 83.33 N/A N/A 549550 chr9 140205997 79.17 N/A N/A 549 550 * Level values provided are theproportion (percentage) of reacted thyroid nodule DNA molecules having auracil at the methylation site of interest. When amplicons generatedfrom reacted thyroid nodule DNA molecules (e.g., by PCR) are used toassess the level of methylation, the values provided correspond to theproportion of amplicons having a thymidine at the nucleotide positionthat corresponds to the methylation site of interest.

In embodiments, the method of detecting methylation or unmethylation ofa thyroid nodule DNA of a subject detects an alteration in methylationincluding increase or loss of uracil level at plurality of methylationsites. In embodiments, the method of detecting methylation orunmethylation of a thyroid nodule DNA of a subject detects an alterationin methylation including increase or loss of thymidine level atplurality of methylation sites. The indicated levels in Tables 1, 2, 3,and 4, are approximate indicated levels, and include values that arewithin about 15%, about 10%, or about 5% above and below the indicatedlevels.

In embodiments, the method detects the uracil level above about athreshold as set forth in Table 2 in subjects with a cancerous thyroidnodule. In embodiments, the method detects the thymidine level aboveabout a threshold as set forth in Table 2 in subjects with a cancerousthyroid nodule.

TABLE 2 Methylation Threshold for Cancerous Thyroid Nodule ChromosomeChromosomal Position Uracil level in reacted thyroid nodule DNA fromcancer tissues is about above indicated level* chr1 11979164 89.29 chr116450525 70.00 chr1 16450542 72.00 chr1 16450545 73.33 chr1 1646998780.00 chr1 17494491 86.00 chr1 25473203 88.89 chr1 38493013 86.36 chr138493030 79.17 chr1 38493074 80.95 chr1 109816092 80.77 chr1 10981611180.77 chr1 110074669 75.00 chr1 110074681 71.43 chr1 110074685 63.16chr1 150949856 89.29 chr1 150949857 88.46 chr1 153540282 78.26 chr1155162704 84.21 chr1 155162714 88.64 chr1 157611881 83.05 chr1 18220532477.50 chr1 204118999 59.09 chr1 206741875 83.33 chr1 206741989 66.67chr1 212841198 85.29 chr1 223403952 79.17 chr1 234342767 76.67 chr103929071 88.68 chr10 30047012 86.84 chr10 79702989 83.33 chr10 8798490586.36 chr10 94838789 63.33 chr10 102131187 90.00 chr10 104196489 75.00chr10 111766879 89.47 chr10 112258886 81.82 chr10 112258984 83.33 chr10112259015 82.61 chr10 120011530 79.55 chr11 821282 89.13 chr11 1218893783.33 chr11 12188948 77.78 chr11 12188995 78.57 chr11 65158294 78.00chr11 65158342 85.00 chr11 65297089 75.00 chr11 66104481 81.58 chr1166104485 83.33 chr11 66104578 81.82 chr11 70236292 89.29 chr11 7023632085.71 chr11 70236331 70.83 chr11 117950310 79.55 chr11 117950329 79.55chr11 117950361 80.00 chr11 117950362 81.82 chr12 679803 86.84 chr1226039132 73.91 chr12 50286016 82.14 chr12 52243258 82.00 chr12 5224328682.50 chr12 56115043 89.29 chr12 66262229 72.22 chr12 66262230 71.74chr12 66262233 68.27 chr12 66262234 71.74 chr12 117580102 84.62 chr12123435962 63.89 chr12 123436011 71.88 chr12 123436065 69.44 chr12123540893 77.27 chr13 46771519 67.65 chr13 46771520 73.91 chr14 3859911865.91 chr14 69170010 86.36 chr14 75701632 68.42 chr14 75701643 68.75chr14 103768055 76.09 chr14 104354645 72.92 chr14 104360487 83.33 chr1541068807 69.12 chr15 61152225 83.33 chr15 61152253 86.67 chr15 6115231386.67 chr15 70667596 83.33 chr15 70767206 90.00 chr15 77989064 73.53chr15 85402496 82.10 chr15 85402497 79.49 chr15 99417337 88.89 chr161231873 86.36 chr16 23135832 87.50 chr16 29616265 85.71 chr16 3100954784.00 chr16 31009548 85.00 chr16 31009590 85.00 chr16 57793674 80.95chr16 57793715 85.71 chr16 57793727 80.95 chr16 70771056 68.75 chr1670771079 63.33 chr16 70771141 65.79 chr16 77332010 72.58 chr16 7854037875.76 chr16 84262419 87.23 chr17 16323460 85.00 chr17 16323473 84.21chr17 16924561 80.36 chr17 16924562 75.71 chr17 16924594 75.71 chr1717717918 72.73 chr17 17718591 84.38 chr17 18139506 82.81 chr17 3967757071.88 chr17 43200096 77.78 chr17 43200239 85.00 chr17 48178379 83.33chr17 48764165 88.89 chr17 55701962 68.75 chr17 73993165 90.00 chr1775827716 78.57 chr17 76882243 61.54 chr17 78765910 88.71 chr17 7954447883.15 chr17 80696474 60.00 chr18 21440760 67.86 chr18 45555437 66.18chr18 45555438 73.68 chr18 46547891 76.09 chr18 55888885 75.47 chr1856452096 90.00 chr18 56452476 81.82 chr18 76002973 81.58 chr18 7733109081.03 chr19 677895 85.29 chr19 884044 76.92 chr19 884059 76.92 chr19884105 84.62 chr19 884115 84.62 chr19 1136511 86.96 chr19 1177605 73.68chr19 1177612 72.73 chr19 1177640 81.82 chr19 1860601 88.46 chr191860607 82.81 chr19 2503954 90.00 chr19 4052713 85.56 chr19 405271485.14 chr19 4052749 84.62 chr19 4374591 82.14 chr19 5048836 77.27 chr195048867 70.59 chr19 5048877 73.53 chr19 8367279 75.00 chr19 1025457776.25 chr19 10254578 79.17 chr19 13203671 75.86 chr19 15375465 72.22chr19 17218912 81.25 chr19 18157161 88.24 chr19 18157221 86.76 chr1918157258 65.22 chr19 30606642 80.56 chr19 47316268 76.67 chr2 2041244185.71 chr2 65064865 64.71 chr2 70823641 79.03 chr2 74454110 70.00 chr2128158884 85.00 chr2 128158910 77.50 chr2 203114171 79.63 chr2 23834146586.36 chr2 238341542 90.00 chr2 238341546 87.50 chr2 238774763 67.57chr20 31126186 87.50 chr20 31126189 84.21 chr20 36771969 79.31 chr2048993661 80.00 chr20 58406398 89.66 chr20 61976049 87.93 chr20 6197607389.66 chr22 19738127 70.59 chr22 35965176 76.32 chr22 36549809 83.33chr22 36973375 80.43 chr22 39662794 84.62 chr22 45622980 85.00 chr314180153 57.89 chr3 52525100 79.41 chr3 62589658 87.50 chr3 6538831771.43 chr3 65388388 79.31 chr3 73599302 85.11 chr3 197093846 80.00 chr43743223 68.18 chr4 5755716 85.48 chr4 5755717 80.00 chr4 5755728 82.26chr4 5755729 79.17 chr4 5755734 79.17 chr4 57548289 80.23 chr5 111828073.08 chr5 34564389 89.29 chr5 73871907 89.47 chr5 78013596 70.00 chr578013643 80.00 chr5 137802650 72.73 chr5 139051189 84.09 chr5 16783822168.18 chr6 7236568 84.43 chr6 41438575 89.66 chr6 43464150 75.76 chr7989235 76.67 chr7 2673543 82.14 chr7 105079565 78.75 chr7 10507963171.25 chr7 151425103 86.96 chr7 151425104 76.19 chr8 11764017 80.77 chr8141320393 75.00 chr8 141320410 85.00 chr9 6566568 86.84 chr9 12612674186.11 chr9 136077410 73.91 chr9 139655018 83.33 chr9 140205985 75.00chr9 140205989 83.33 chr9 140205997 79.17 * Level values provided arethe proportion (percentage) of reacted thyroid nodule DNA moleculeshaving a uracil at the methylation site of interest. When ampliconsgenerated from reacted thyroid nodule DNA molecules (e.g., by PCR) areused to assess the level of methylation, the values provided correspondto the proportion of amplicons having a thymidine at the nucleotideposition that corresponds to the methylation site of interest.

In embodiments, the uracil level is above a threshold as set forth inTable 3 in subjects with benign thyroid nodules. In embodiments, thethymidine level is above a threshold as set forth in Table 3 in subjectswith benign thyroid nodules.

TABLE 3 Threshold for Benign Thyroid Nodule Chromosome ChromosomalPosition Uracil level in reacted thyroid nodule DNA from benign tissuesis about above indicated level* chr1 2996653 88.84 chr1 27640460 80.56chr10 126172714 80.00 chr10 126172747 84.62 chr11 36057726 79.63 chr1148070143 84.38 chr11 48070163 87.50 chr11 48070166 84.38 chr11 4807017484.48 chr12 77266621 73.53 chr14 97524282 88.89 chr14 104209000 80.77chr14 104209068 83.33 chr15 77984014 88.89 chr16 3023231 84.00 chr1679333435 89.61 chr17 1509928 88.46 chr17 1509945 88.46 chr17 150995283.93 chr17 1509953 85.00 chr17 7644013 85.42 chr17 48596391 88.64 chr195013982 83.33 chr19 10463956 86.73 chr19 10464137 89.29 chr19 4717303788.64 chr2 3454277 84.78 chr2 8793724 78.57 chr2 55289272 75.00 chr2122014529 86.36 chr2 218221671 85.19 chr22 38307317 89.66 chr4 837286185.71 chr6 3394325 87.84 chr6 3887581 85.71 chr6 1.59E+08 86.84 chr822548399 88.16 chr8 22548483 87.50 chr8 1.34E+08 80.00 chr9 1619786286.36 * Level values provided are the proportion (percentage) of reactedthyroid nodule DNA molecules having a uracil at the methylation site ofinterest. When amplicons generated from reacted thyroid nodule DNAmolecules (e.g., by PCR) are used to assess the level of methylation,the values provided correspond to the proportion of amplicons having athymidine at the nucleotide position that corresponds to the methylationsite of interest.

In embodiments, the uracil level is below a threshold as set forth inTable 4 in subjects with benign thyroid nodule. In embodiments, thethymidine level is below a threshold as set forth in Table 4 in subjectswith benign thyroid nodule.

TABLE 4 Methylation Threshold for Benign Thyroid Nodule ChromosomeChromosomal Position Uracil level in reacted thyroid nodule DNA frombenign tissues is about below indicated level* chr1 12655938 69.23 chr129565080 60.00 chr1 46713777 73.33 chr1 46914121 60.00 chr1 4695574477.78 chr1 55008344 60.00 chr1 156676611 84.62 chr1 212587673 80.00 chr1233430972 86.67 chr10 116391763 75.00 chr11 556355 75.00 chr11 6860876773.33 chr11 115530032 79.49 chr11 119293593 60.00 chr12 31004558 81.82chr12 45610695 83.33 chr12 45610701 86.67 chr12 45610702 89.47 chr1245610706 80.00 chr12 54145732 82.35 chr12 54145741 76.47 chr12 5414582570.59 chr13 20735797 82.35 chr13 23500419 68.42 chr13 53313426 60.00chr13 113807393 27.27 chr14 90850454 54.55 chr14 103541602 52.00 chr1565186440 55.56 chr15 68851629 63.64 chr15 75251486 60.00 chr15 8395208172.73 chr16 1458639 75.00 chr16 88701114 66.67 chr16 89988308 83.33chr16 89988644 47.37 chr17 35278031 28.42 chr17 40826257 23.81 chr1743037426 33.33 chr17 43510142 81.82 chr17 47987828 69.23 chr17 7358459960.00 chr18 19751759 33.33 chr18 56887181 60.00 chr19 3434917 40.00chr19 3434921 42.86 chr19 3434930 57.14 chr19 3434939 71.43 chr193434952 71.43 chr19 3434954 60.00 chr19 3434962 71.43 chr19 343496471.43 chr19 3434979 66.67 chr19 3434985 55.56 chr19 8428573 75.00 chr1913266925 66.67 chr19 13266934 66.67 chr19 13266970 63.64 chr19 1384214276.47 chr19 14248494 73.91 chr19 17346702 85.71 chr19 17346735 78.95chr19 18415877 47.83 chr19 18415890 47.83 chr19 35531842 83.33 chr1944303112 77.78 chr19 47778278 66.67 chr19 47778298 83.33 chr2 4232940278.95 chr2 42329494 60.00 chr2 73143689 77.78 chr2 219745335 81.82 chr2034206950 76.47 chr20 62588571 50.00 chr20 62588579 38.46 chr22 3744795373.33 chr22 37914998 69.23 chr3 13323642 72.73 chr3 45209073 60.00 chr345209207 83.33 chr3 195636893 84.62 chr5 177541401 69.23 chr5 18001867272.73 chr5 180101026 64.71 chr6 7728692 73.33 chr6 34203617 45.45 chr637751320 78.57 chr6 41410682 77.78 chr6 41438516 39.13 chr7 7350860285.71 chr8 21647308 71.43 chr9 34591313 80.00 chr9 98225096 22.22 chr9132083428 70.59 * Level values provided are the proportion (percentage)of reacted thyroid nodule DNA molecules having a uracil at themethylation site of interest. When amplicons generated from reactedthyroid nodule DNA molecules (e.g., by PCR) are used to assess the levelof methylation, the values provided correspond to the proportion ofamplicons having a thymidine at the nucleotide position that correspondsto the methylation site of interest.

In embodiments, the method of detecting methylation or unmethylation ofa thyroid nodule DNA is of a candidate thyroid cancer patient. Inembodiments, the subject is suspected of having thyroid cancer. Inembodiments, the subject has thyroid cancer.

In embodiments, the method of detecting methylation or unmethylation ofa thyroid nodule DNA is based on the level of uracil as set forth Table2, in which the uracil level above the threshold identifies the thyroidnodule as a cancerous thyroid nodule. In embodiments, the method ofdetecting methylation or unmethylation of a thyroid nodule DNA is basedon a level of thymidine indicated in Table 2, in which the thymidinelevel above the threshold identifies the thyroid nodule as a cancerousthyroid nodule. In embodiments, the level is the proportion of molecules(e.g., in a plurality of reacted thyroid nodule DNA molecules or aplurality of reacted thyroid nodule DNA amplicons) having a uracil orthymidine as determined by a quantitation method. Non-limiting examplesof quantitation methods include sequencing and microarray methods.

In embodiments, the method of detecting methylation or unmethylation ofa thyroid nodule DNA is based on the level of uracil as set forth Table3, in which the uracil level above the threshold identifies the thyroidnodule as a benign thyroid nodule. In embodiments, the method ofdetecting methylation or unmethylation of a thyroid nodule DNA is basedon a level of thymidine indicated in Table 3, in which the thymidinelevel above the threshold identifies the thyroid nodule as a benignthyroid nodule. In embodiments, the level is the proportion of molecules(e.g., in a plurality of reacted thyroid nodule DNA molecules or aplurality of reacted thyroid nodule DNA amplicons) having a uracil orthymidine as determined by a quantitation method.

In embodiments, the method of detecting methylation or unmethylation ofa thyroid nodule DNA is based on the level of uracil as set forth Table4, in which the uracil level below the threshold identifies the thyroidnodule as a benign thyroid nodule. In embodiments, the method ofdetecting methylation or unmethylation of a thyroid nodule DNA is basedon a level of thymidine indicated in Table 4, in which the thymidinelevel below the threshold identifies the thyroid nodule as a benignthyroid nodule. In embodiments, the level is the proportion of molecules(e.g., in a plurality of reacted thyroid nodule DNA molecules or aplurality of reacted thyroid nodule DNA amplicons) having a uracil orthymidine as determined by a quantitation method.

In embodiments, the thyroid nodule is a specimen obtained by biopsy orby surgical resection of a subject.

In embodiments, the subject has undergone thyroid surgery, radiationtherapy, radioactive iodine therapy, chemotherapy, thyroid hormonetherapy, and administration of an active agent before the subjectundergoes the method of detecting methylation or unmethylation of athyroid nodule DNA.

In embodiments, the method includes a determination of prognosis forlocal recurrence in thyroid cancer. In embodiments, the method includesdetermination of prognosis of distant recurrence of thyroid cancer.

In embodiments, the method of detecting DNA methylation level in DNA ofthyroid nodule may lead to changes in therapeutic regimen for treatingthe subject. In embodiments a subject identified as having thyroidcancer may be treated with tyrosine kinase inhibitors.

In embodiments, the active agent administered to a subject before orafter detecting the level of methylation or unmethylation is:Cabozantinib-S-Malate, Caprelsa® (Vandetanib), Cometriq®(Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate,Lenvima® (Lenvatinib Mesylate), Nexavar® (Sorafenib Tosylate), SorafenibTosylate, and/or Vandetanib.

Method of Determining Thyroid Cancer or Risk of Developing ThyroidCancer

In an aspect, provided herein is a method of determining a thyroidcancer or risk of developing thyroid cancer in a subject in needthereof. The method involves:

-   (i) isolating a thyroid nodule DNA molecule from a thyroid nodule of    the subject thereby forming an isolated thyroid nodule DNA molecule;-   (ii) contacting the isolated thyroid nodule DNA molecule with a    bisulfite salt (such as sodium bisulfite) thereby forming a reacted    thyroid nodule DNA molecule; and-   (iii) detecting the presence or absence of uracil in the reacted    thyroid nodule DNA molecule at a methylation site set forth in Table    1; thereby detecting the thyroid cancer in the subject.

In an aspect, provided herein is a method of detecting a thyroid canceror risk of developing thyroid cancer in a subject in need thereof,comprising (i) isolating a plurality of thyroid nodule DNA moleculesfrom the thyroid nodule of the subject thereby forming a plurality ofisolated thyroid nodule DNA molecules, (ii) contacting the plurality ofisolated thyroid nodule DNA molecules with the bisulfite salt therebyforming a plurality of reacted thyroid nodule DNA molecules, (iii)detecting the level of reacted thyroid nodule DNA molecules in theplurality of reacted thyroid nodule DNA molecules having a uracil at amethylation site set forth in Table 1; thereby detecting the thyroidcancer in the subject.

In an aspect, provided herein is a method of detecting a thyroid canceror risk of developing thyroid cancer in a subject in need thereof,comprising (i) isolating a plurality of thyroid nodule DNA moleculesfrom the thyroid nodule of the subject thereby forming a plurality ofisolated thyroid nodule DNA molecules, (ii) contacting the plurality ofisolated thyroid nodule DNA molecules with the bisulfite salt therebyforming a plurality of reacted thyroid nodule DNA molecules, (iii)detecting the presence or absence of uracil in a reacted thyroid noduleDNA molecule at a methylation site set forth in Table 1, therebydetecting methylation or unmethylation of the thyroid nodule DNAmolecule of the subject.

In an aspect, provided herein is a method of detecting a thyroid canceror risk of developing thyroid cancer in a subject in need thereof. Themethod includes: (i) isolating a thyroid nodule DNA molecule from athyroid nodule of the subject thereby forming an isolated thyroid noduleDNA molecule, (ii) contacting the isolated thyroid nodule DNA moleculewith a bisulfite salt (such as sodium bisulfite) thereby forming areacted thyroid nodule DNA molecule, (iii) amplifying the reactedthyroid nodule DNA molecule thereby forming a reacted thyroid nodule DNAamplicon molecule, (iv) detecting the presence or absence of thymidinein a reacted thyroid nodule DNA amplicon molecule at a methylation siteset forth in Table 1, thereby detecting methylation or unmethylation ofthe thyroid nodule DNA molecule of the subject. In embodiments,contacting the isolated thyroid nodule DNA with a bisulfite saltcomprises adding a solution comprising the bisulfite salt to a solutioncomprising the isolated single stranded DNA.

In an aspect, provided herein is a method of detecting a thyroid canceror risk of developing thyroid cancer in a subject in need thereof,comprising (i) isolating a plurality of thyroid nodule DNA moleculesfrom the thyroid nodule of the subject thereby forming a plurality ofisolated thyroid nodule DNA molecules, (ii) contacting the plurality ofisolated thyroid nodule DNA molecules with the bisulfite salt therebyforming a plurality of reacted thyroid nodule DNA molecules, (iii)amplifying the plurality of reacted thyroid nodule DNA molecules therebyforming a plurality of reacted thyroid nodule DNA amplicon molecules,(iv) detecting one or more thyroid nodule DNA amplicon molecules withinthe plurality of reacted thyroid nodule DNA amplicon molecules having athymidine at a methylation site set forth in Table 1, thereby detectingmethylation or unmethylation of the thyroid nodule DNA molecule of thesubject.

In embodiments, detecting one or more thyroid nodule DNA ampliconmolecules comprises detecting the level of one or more one or morethyroid nodule DNA amplicon molecules. In embodiments, detecting one ormore thyroid nodule DNA amplicon molecules comprises detecting the levelof reacted thyroid nodule DNA amplicon molecules in the plurality ofreacted thyroid nodule DNA amplicon molecules having a thymidine at amethylation site set forth in Table 1, thereby detecting the level ofmethylation or unmethylation in the plurality of thyroid nodule DNAmolecules of the subject.

In embodiments, detecting a level includes determining the number (e.g.quantitating) or molecules having, e.g., a thymidine or a uracil. Inembodiments, detecting a level includes detecting the portion orproportion of a population or plurality of molecules having, e.g., athymidine or a uracil.

In embodiments, contacting the isolated thyroid nodule DNA with abisulfite salt comprises adding a solution comprising the bisulfite saltto a solution comprising the isolated thyroid nodule DNA.

In embodiments, the method of determining a thyroid cancer or risk ofdeveloping thyroid cancer in a subject in need thereof includesselecting a subject that has or is at risk for developing thyroidcancer. In embodiments, the subject (a) is a woman; (b) is about 20 toabout 55 years old; (c) has a mutated Ret Proto-Oncogene; (d) has agrandparent, parent, or sibling who has been diagnosed with thyroidcancer; (e) self-identifies as being Caucasian or Asian; and/or (f) hasor has had breast cancer.

In embodiments, the method includes detecting methylation orunmethylation at a plurality of methylation sites set forth in Table 1.In embodiments, the plurality of methylation sites comprises at leastabout 2, 3, 4, 5, 10, 25, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300,350, 400, 450, 500, or 550, or 5-550 methylation sites. In embodiments,the plurality of methylation sites comprises less than about 550, 500,450, 400, 350, 300, 250, 200, 150, 100, 90, 85, 80, 75, 50, 25, or 10methylation sites. In embodiments, the plurality of methylation sites isabout 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 50,75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 550, or5-550 methylation sites. In embodiments, the plurality of methylationsites includes two or more methylation sites set forth in Table 1 and noother methylation sites.

In embodiments, a method provided herein is practiced for a subject morethan once over time. In embodiments, methylation or unmethylation ofthyroid nodule DNA from a subject is assessed using a method providedherein at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times. Inembodiments, the method is repeated at least once every 4, 6, 8, 12 or18 months, or at least once every 2, 3, 4, or 5 more years.

In embodiments, the method of determining a thyroid cancer or risk ofdeveloping thyroid cancer in a subject in need thereof includesdetermining alteration in methylation at a plurality of methylationsites set forth in Table 1. In embodiments, the method comprises: (i)isolating DNA from multiple cells of a thyroid nodule of the subjectthereby forming a plurality of isolated thyroid nodule DNA molecules,(ii) contacting the plurality of isolated thyroid nodule DNA moleculeswith a bisulfite salt thereby forming a plurality of reacted thyroidnodule DNA molecules, (iii) detecting the proportion of DNA molecules inthe plurality of reacted thyroid nodule DNA molecules having a uracil ata methylation site set forth in Table 1.

In embodiments, the method of determining a thyroid cancer or risk ofdeveloping thyroid cancer in a subject in need thereof includesalteration, i.e., increase or loss of uracil level at plurality ofmethylation sites. In embodiments, the method of determining a thyroidcancer or risk of developing thyroid cancer in a subject in need thereofincludes alteration, i.e., increase or loss of thymidine level atplurality of methylation sites.

In embodiments, the method of determining a thyroid cancer or risk ofdeveloping thyroid cancer in a subject in need thereof includesdetermining a uracil level which is above a threshold as set forth inTable 2. In embodiments, the method of determining a thyroid cancer orrisk of developing thyroid cancer in a subject in need thereof includesdetermining a thymidine level which is above a threshold indicated inTable 2. In embodiments, the level is the proportion of molecules (e.g.,in a plurality of reacted thyroid nodule DNA molecules or a plurality ofreacted thyroid nodule DNA amplicons) having a uracil or thymidine asdetermined by a quantitation method.

In embodiments, the method of determining a thyroid cancer or risk ofdeveloping thyroid cancer in a subject in need thereof includesdetermining a uracil level which is above a threshold as set forth inTable 3. In embodiments, the method of determining a thyroid cancer orrisk of developing thyroid cancer in a subject in need thereof includesdetermining a thymidine level which is above a threshold indicated inTable 3. In embodiments, the level is the proportion of molecules (e.g.,in a plurality of reacted thyroid nodule DNA molecules or a plurality ofreacted thyroid nodule DNA amplicons) having a uracil or thymidine asdetermined by a quantitation method.

In embodiments, the method of determining a thyroid cancer or risk ofdeveloping thyroid cancer in a subject in need thereof includesdetermining a uracil level which is below a threshold as set forth inTable 4. In embodiments, the method of determining a thyroid cancer orrisk of developing thyroid cancer in a subject in need thereof includesdetermining a thymidine level which is below a threshold indicated inTable 4. In embodiments, the level is the proportion of molecules (e.g.,in a plurality of reacted thyroid nodule DNA molecules or a plurality ofreacted thyroid nodule DNA amplicons) having a uracil or thymidine asdetermined by a quantitation method.

In embodiments, the method of determining a thyroid cancer or risk ofdeveloping thyroid cancer involves a candidate thyroid cancer patient.In embodiments, the subject is suspected of having thyroid cancer. Inembodiments, the subject has thyroid cancer.

In embodiments, the method of determining a thyroid cancer or risk ofdeveloping thyroid cancer in a subject in need thereof includesdetermining a uracil level in which a threshold above the threshold setforth in Table 2 identifies the thyroid nodule as a cancerous thyroidnodule. In embodiments, the method of determining a thyroid cancer orrisk of developing thyroid cancer in a subject in need thereof includesdetermining a thymidine level in which a threshold above the thresholdindicated in Table 2 identifies the thyroid nodule as a cancerousthyroid nodule. In embodiments, the level is the proportion of molecules(e.g., in a plurality of reacted thyroid nodule DNA molecules or aplurality of reacted thyroid nodule DNA amplicons) having a uracil orthymidine as determined by a quantitation method.

In embodiments, the method of determining a thyroid cancer or risk ofdeveloping thyroid cancer in a subject in need thereof includesdetermining a uracil level in which a threshold above the threshold setforth in Table 3 identifies the thyroid nodule as a benign thyroidnodule. In embodiments, the method of determining a thyroid cancer orrisk of developing thyroid cancer in a subject in need thereof includesdetermining a thymidine level in which a threshold above the thresholdindicated in Table 3 identifies the thyroid nodule as a benign thyroidnodule. In embodiments, the level is the proportion of molecules (e.g.,in a plurality of reacted thyroid nodule DNA molecules or a plurality ofreacted thyroid nodule DNA amplicons) having a uracil or thymidine asdetermined by a quantitation method.

In embodiments, the method of determining a thyroid cancer or risk ofdeveloping thyroid cancer in a subject in need thereof includesdetermining a uracil level in which a threshold below the threshold setforth in Table 4 identifies the thyroid nodule as a benign thyroidnodule. In embodiments, the method of determining a thyroid cancer orrisk of developing thyroid cancer in a subject in need thereof includesdetermining a thymidine level in which a threshold below the thresholdindicated in Table 4 identifies the thyroid nodule as a benign thyroidnodule. In embodiments, the level is the proportion of molecules (e.g.,in a plurality of reacted thyroid nodule DNA molecules or a plurality ofreacted thyroid nodule DNA amplicons) having a uracil or thymidine asdetermined by a quantitation method.

In embodiments, the method of determining a thyroid cancer or risk ofdeveloping thyroid cancer in a subject in need thereof includesdetermining a uracil level in DNA of a thyroid nodule specimen obtainedby biopsy or by surgical resection of a subject. In embodiments, themethod of determining a thyroid cancer or risk of developing thyroidcancer in a subject in need thereof includes determining a thymidinelevel in DNA of a thyroid nodule specimen obtained by biopsy or bysurgical resection of a subject.

In embodiments, the method of determining a thyroid cancer or risk ofdeveloping thyroid cancer is of a subject who has previously undergonethyroid surgery, radiation therapy, radioactive iodine therapy,chemotherapy, thyroid hormone therapy, and/or administration of anactive agent, before the determination.

In embodiments, a subject having thyroid cancer or at risk of developingthyroid cancer was administered an active agent: Cabozantinib-S-Malate,Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate), DoxorubicinHydrochloride, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate),Nexavar (Sorafenib Tosylate), Sorafenib Tosylate, and/or Vandetanib.

In embodiments, the method of determining a thyroid cancer may lead tochanges in therapeutic regimen for treating the subject. In embodimentsa subject identified as having thyroid cancer may be treated withtyrosine kinase inhibitors. In embodiments, a subject identified ashaving thyroid cancer or being at risk of developing thyroid canceraccording to a method disclosed herein is advised and/or directed toreceive additional screening and/or treatment for thyroid cancer.

In embodiments, the active agent administered to a subject afterdetermining thyroid cancer is: Cabozantinib-S-Malate, Caprelsa(Vandetanib), Cometriq (Cabozantinib-S-Malate), DoxorubicinHydrochloride, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate),Nexavar (Sorafenib Tosylate), Sorafenib Tosylate, and/or Vandetanib.

Method of Treating Thyroid Cancer

Also provided herein is a method of treating thyroid cancer in a subjectby administering to the subject an active agent for treating thyroidcancer, in which the subject is identified for treatment by a methodincluding isolating a thyroid nodule DNA molecule from a thyroid noduleof the subject thereby forming an isolated thyroid nodule DNA molecule;contacting the isolated thyroid nodule DNA molecule with a bisulfitesalt (such as sodium bisulfite) thereby forming a reacted thyroid noduleDNA molecule; and detecting the presence or absence of uracil in thereacted thyroid nodule DNA molecule at a methylation site set forth inTable 1; thereby detecting the thyroid cancer in the subject. Inembodiments, contacting the isolated thyroid nodule DNA with a bisulfitesalt comprises adding a solution comprising the bisulfite salt to asolution comprising the isolated thyroid nodule DNA.

In embodiments, the method includes detecting methylation orunmethylation at a plurality of methylation sites set forth in Table 1.In embodiments, the plurality of methylation sites comprises at leastabout 2, 3, 4, 5, 10, 25, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300,350, 400, 450, 500, or 550, or 5-550 methylation sites. In embodiments,the plurality of methylation sites comprises less than about 550, 500,450, 400, 350, 300, 250, 200, 150, 100, 90, 85, 80, 75, 50, 25, or 10methylation sites. In embodiments, the plurality of methylation sites isabout 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 50,75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 550, or5-550 methylation sites. In embodiments, the plurality of methylationsites includes two or more methylation sites set forth in Table 1 and noother methylation sites.

In embodiments, a method provided herein is practiced for a subject morethan once over time. In embodiments, methylation or unmethylation ofthyroid nodule DNA from a subject is assessed using a method providedherein at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times. Inembodiments, the method is repeated at least once every 4, 6, 8, 12 or18 months, or at least once every 2, 3, 4, or 5 more years.

In embodiments, the method of treating a thyroid cancer in a subject inneed thereof includes determining alteration in methylation at aplurality of methylation sites set forth in Table 1.

In embodiments, the method of treating a thyroid cancer in a subject inneed thereof includes alteration which includes increase or loss ofuracil level at plurality of methylation sites.

In embodiments, the method of treating a thyroid cancer in a subject inneed thereof includes determining a uracil level which is above athreshold as set forth in Table 2. In embodiments, the method oftreating a thyroid cancer in a subject in need thereof includesdetermining a thymidine level which is above a threshold indicated inTable 2. In embodiments, the level is the proportion of molecules (e.g.,in a plurality of reacted thyroid nodule DNA molecules or a plurality ofreacted thyroid nodule DNA amplicons) having a uracil or thymidine asdetermined by a quantitation method.

In embodiments, the method of treating a thyroid cancer in a subject inneed thereof includes determining a uracil level which is above athreshold as set forth in Table 3. In embodiments, the method oftreating a thyroid cancer in a subject in need thereof includesdetermining a thymidine level which is above a threshold indicated inTable 3. In embodiments, the level is the proportion of molecules (e.g.,in a plurality of reacted thyroid nodule DNA molecules or a plurality ofreacted thyroid nodule DNA amplicons) having a uracil or thymidine asdetermined by a quantitation method.

In embodiments, the method of treating a thyroid cancer in a subject inneed thereof includes determining a uracil level which is below athreshold as set forth in Table 4. In embodiments, the method oftreating a thyroid cancer in a subject in need thereof includesdetermining a thymidne level which is below a threshold indicated inTable 4. In embodiments, the level is the proportion of molecules (e.g.,in a plurality of reacted thyroid nodule DNA molecules or a plurality ofreacted thyroid nodule DNA amplicons) having a uracil or thymidine asdetermined by a quantitation method.

In embodiments, the method of treating a thyroid cancer is in a subjectwho has undergone surgery, radiation therapy, radioactive iodinetherapy, chemotherapy, or thyroid hormone therapy, before the detectingthyroid cancer.

In embodiments, an active agent administered to a subject for treatingthyroid cancer: Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq(Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate,Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate), SorafenibTosylate, and/or Vandetanib.

In embodiments, the subject has or is at risk of papillary thyroidcancer, follicular thyroid cancer, medullary thyroid cancer, oranaplastic thyroid cancer.

In embodiments, the method includes determining a papillary thyroidcarcinoma (PTC) methylation alteration score for the subject, whereinthe PTC methylation alteration score is equal to the number ofmethylation sites in Table 1 having a uracil level equal to or greaterthan the corresponding threshold level set forth in Table 2.

In embodiments, the method includes determining a PTC methylationalteration score for the subject, wherein the PTC methylation alterationscore is equal to the number of methylation sites in Table 1 having athymidine level equal to or greater than the corresponding thresholdlevel set forth in Table 2.

In embodiments, the method includes determining a benign thyroid nodule(BTN) methylation alteration score for said subject, wherein the BTNmethylation alteration score is equal to: (a) the number of methylationsites in Table 1 having a uracil level equal to or greater than thecorresponding threshold level set forth in Table 3; (b) the number ofmethylation sites in Table 1 having a uracil level equal to or less thanthe corresponding threshold level set forth in Table 4; or (c) thenumber of methylation sites in Table 1 having a uracil level equal to orgreater than the corresponding threshold level set forth in Table 3 plusthe number of methylation sites in Table 1 having a uracil level equalto or less than the corresponding threshold level set forth in Table 4.

In embodiments, the method includes determining a benign thyroid nodule(BTN) methylation alteration score for said subject, wherein the BTNmethylation alteration score is equal to: (a) the number of methylationsites in Table 1 having a thymidine level equal to or greater than thecorresponding threshold level set forth in Table 3; (b) the number ofmethylation sites in Table 1 having a thymidine level equal to or lessthan the corresponding threshold level set forth in Table 4; or (c) thenumber of methylation sites in Table 1 having a thymidine level equal toor greater than the corresponding threshold level set forth in Table 3plus the number of methylation sites in Table 1 having a thymidine levelequal to or less than the corresponding threshold level set forth inTable 4.

In embodiments, the method comprises calculating a Composite Cancer RiskScore for the subject. In embodiments, the Composite Cancer Risk Scorefor the subject equals: [the PTC methylation alteration score for saidsubject]/[BTN methylation alteration score for said subject]. Inembodiments, the Composite Cancer Risk Score for the subject equals:[(the PTC methylation alteration score for said subject) + 1]/[(BTNmethylation alteration score for said subject) +1].

In embodiments, the subject is identified as being at risk of developingthyroid cancer or diagnosed as having thyroid cancer if (a) the PTCmethylation alteration score for the subject is at least 5, 6, 7, 8, 9,or 10; (b) the BTN methylation alteration score for the subject is atleast 5, 6, 7, 8, 9, or 10; and/or (c) the Composite Cancer Risk Scorefor the subject is at least about 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,2.8, 2.9, or 3.0.

In embodiments, the subject receives treatment (e.g., is directed oradvised to receive treatment) for thyroid cancer or is directed toreceive additional screening for thyroid cancer if (a) the PTCmethylation alteration score for the subject is at least 5, 6, 7, 8, 9,or 10; (b) the BTN methylation alteration score for the subject is atleast 5, 6, 7, 8, 9, or 10; and/or (c) the Composite Cancer Risk Scorefor the subject is at least about 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,2.8, 2.9, or 3.0.

Target Sites for Methylation Level of Thyroid Nodule

In another aspect, provided herein is a deoxyribonucleic acid 5 to 100,5 to 300, 5 to 300, or at least about 5, 50, 100, 150, 200, 250, 300, ormore nucleotides in length including a uracil-containing sequenceidentical to the sequence of at least 5 contiguous nucleotides within asequence including SEQ ID NO:1 to SEQ ID NO:550.

SEQ ID NO: 1 to SEQ ID NO:500 are 300bp length sequences that includethe target sites (i.e., methylation sites of interest). The sequencesprovided are as modified after bisulfite conversion. Therefore “C” inthe non-CpG context becomes “U”, and C in the CpG context is designatedas R or X (either “D” either “C”), where X is the target site. The DNAstrands (sense and antisense) are no longer complementary afterbisulfite conversion. Therefore, each DNA strand is identified with itsunique sequence, and is designated as “forward” and “reverse”respectively, in Table 1.

The sequences listed in Table 1 are provided below with their respectivesequence identification number.

TABLE 1 SEQ ID NO: Sequence 1TUUTTAGUUUTURGTGGRGUUAGAGTTGGTTGUUTUAGTAGRGRGTGUUUAUURGGUUUAAAGUTGTTUTGUAGUTGGTUAUTGTGGGAGAAGAGAUTGGAAAAGTTUAAAGGTGGAGAGGRGGUAGRGATUTGGAGUAUTTTTURGUAXGUTGTAAUUUUTGAGAAGAAAUAAAGAGGAAARGAGGUTGTTTAGATAATUURGGGUUUTGGTGUTTGUATTTAGAAAAATTAGGUUUTUTTGAAAAATTAUAGAATTATGUTGUUAGTGTUAGGTTUUUAGATAATGATGTGTUTGTGT2UAUAGAUAUATUATTATUTGGGAAUUTGAUAUTGGUAGUATAATTUTGTAATTTTTUAAGAGGGUUTAATTTTTUTAAATGUAAGUAUUAGGGUURGGGATTATUTAAAUAGUUTRGTTTUUTUTTTGTTTUTTUTUAGGGGTTAUAGXGTGRGGAAAAGTGUTUUAGATRGUTGURGUUTUTUUAUUTTTGAAUTTTTUUAGTUTUTTUTUUUAUAGTGAUUAGUTGUAGAAUAGUTTTGGGURGGGTGGGUARGRGUTAUTGAGGUAAUUAAUTUTGGRGUUARGGAGGGUTAAGGAU3GGGTGAUUAGTGUUAUTAAAAGUAGAGUTTGAGTTTAUTUTUATAAUUATRGGUTGTGGGUUAGAUATTTGGUTGUTTTGUAGGUAGAUUAGGUTTUURGGTGAGTUATGUTGUTTAAAATGUTGTUTGGGAARGUAGAGAAAGTUTAAAXGUUAAGARGUTGAGGAUAGUUURGUAGGTGGAUTGUUATGUURGGUTRGGUUUUTTTTTGGTUUUUAGAGTGGAUUUTTUTUUTUUUUAUAGAGGGGAGGUATUTGATGGTGGUTTUAGUAGAUAAUUTGGAGAAGAAUUAUTUAGGGT4AUUUTGAGTGGTTUTTUTUUAGGTTGTUTGUTGAAGUUAUUATUAGATGUUTUUUUTUTGTGGGGAGGAGAAGGGTUUAUTUTGGGGAUUAAAAAGGGGURGAGURGGGUATGGUAGTUUAUUTGRGGGGUTGTUUTUAGRGTUTTGGXGTTTAGAUTTTUTUTGRGTTUUUAGAUAGUATTTTAAGUAGUATGAUTUAURGGGAAGUUTGGTUTGUUTGUAAAGUAGUUAAATGTUTGGUUUAUAGURGATGGTTATGAGAGTAAAUTUAAGUTUTGUTTTTAGTGGUAUTGGTUAUUU5CAGUTGGGGAGGGGAUAGGGTAGGTGGUTGUAGAAGGGGGUTGGGTTGAGGTUTUAGGTGUAGARGAGGAGGGGUTGGGRGGAGGGGGTGAGGAGGGGAGURGGGUTGGGGGURGGGGRGUTGUTGGGGTUUUUUTUURGUUURGGGAUXGTURGUTUTTGUUUAGAUURGTRGGTAAAUAGARGURGTGATGTUARGGGRGURGUTGAUUTGTGGUTGAAUURGGAGUTGTAAATGAGATGUAAGGTGUUAGUAGUUTURGGURGUAGGGUUTARGAGUUAUARGRGUTUUTURGURGG6URGGRGGAGGAGRGRGTGTGGUTRGTAGGUUUTGRGGURGGAGGUTGUTGGUAUUTTGUATUTUATTTAUAGUTURGGGTTUAGUUAUAGGTUAGRGGRGUURGTGAUATUARGGRGTUTGTTTAURGARGGGTUTGGGUAAGAGRGGAXGGTUURGGGGRGGGAGGGGGAUUUUAGUAGRGUUURGGUUUUUAGUURGGUTUUUUTUUTUAUUUUUTURGUUUAGUUUUTUUTRGTUTGUAUUTGAGAUUTUAAUUUAGUUUUUTTUTGUAGUUAUUTAUUUTGTUUUUTUUUUAGUTG7TTTTUTGTAAAATGGGGURGUUUAUAAAAUTUATAAUAAAGTGTTGAGGTTURGAUAAGURGAAAUUTGTGAAAAGUTTGTGTAAAUUTUAGAGUTGTAUATGGATGGTTGAAGGATUTATTTRGAUAGUTURGGGGAGUXGTGGGAGGGAAGUTGAXGGXGGUTUTTGUTGTTUTUUTAUUTUUUAGUUUTUURGAAGAUTUTGAGUAGUUTGGAGATUAAAGGTGATTGGGGUUTGUTGGUATGGAGGURGGGUTRGGUAGAAUUTGUTTUURGGUUUUUTGUUUAUUTUUUAUUUAU8GTGGGTGGGAGGTGGGUAGGGGGURGGGAAGUAGGTTUTGURGAGUURGGUUTUUATGUUAGUAGGUUUUAATUAUUTTTGATUTUUAGGUTGUTUAGAGTUTTRGGGAGGGUTGGGAGGTAGGAGAAUAGUAAGAGUXGUXGTUAGUTTUUUTUUUAXGGUTUUURGGAGUTGTRGAAATAGATUUTTUAAUUATUUATGTAUAGUTUTGAGGTTTAUAUAAGUTTTTUAUAGGTTTRGGUTTGTRGGAAUUTUAAUAUTTTGTTATGAGTTTTGTGGGRGGUUUUATTTTAUAGAAAA9TGAGUAGTGTTTUAGRGUUUAGAGAGAUAUTGTGGAGAAGGTUUAUUAGGATGUUTAUUTGUUTTAUAUAAGAGUUTAAUTTTGGUAUAUUTGTGGUAUAUUTGTGGAGAGUTGTTUTGGUUURGGTTGTUTGGUAGGUUTGGGUTAUTUXGAGUAGGGGAAUTGGGGUAUAGTGGUTGUAUUTURGGUTATAUUUTGGTTTTTUUAGTTUUTGATGUURGUUUUTUAGGTGGUAGUATGAGGTGAUTUAGGGAUAGARGUUUTTATRGTGARGUAAGTUUAGUUUUUAGTGGAGUUUUT10AGGGGUTUUAUTGGGGGUTGGAUTTGRGTUARGATAAGGGRGTUTGTUUUTGAGTUAUUTUATGUTGUUAUUTGAGGGGRGGGUATUAGGAAUTGGAAAAAUUAGGGTATAGURGGAGGTGUAGUUAUTGTGUUUUAGTTUUUUTGUTXGGAGTAGUUUAGGUUTGUUAGAUAAURGGGGUUAGAAUAGUTUTUUAUAGGTGTGUUAUAGGTGTGUUAAAGTTAGGUTUTTGTGTAAGGUAGGTAGGUATUUTGGTGGAUUTTUTUUAUAGTGTUTUTUTGGGRGUTGAAAUAUTGUTUA11TUTTGTAAAATTUUAGAGUUAGGTATAUUUAATTUTGUAARGTGGTAGUTGUATGAUTGTAUAAGTUUUTTAAUAGUAURGGGUUTUAGTGAUATUATUTGTTAAATGGGTTGGTGATGATAATGGTUAGUATTTATGGAGGAGUUUAUAXGGTGUTAAGTGUTTTAUAUATATUAGUTAAUTGAATUUTUAUTGUTGUUAATGAGAUAGGTAUTATTGAATUAGAGGUURGGAGAGAGUTUUARGRGGTTGGTUATAUTGGTGAAGAGUTTGGTTUAATGUUTGGTGAAUTUTRGGUAU12GTGURGAGAGTTUAUUAGGUATTGAAUUAAGUTUTTUAUUAGTATGAUUAAURGRGTGGAGUTUTUTURGGGUUTUTGATTUAATAGTAUUTGTUTUATTGGUAGUAGTGAGGATTUAGTTAGUTGATATGTGTAAAGUAUTTAGUAUXGTGTGGGUTUUTUUATAAATGUTGAUUATTATUATUAUUAAUUUATTTAAUAGATGATGTUAUTGAGGUURGGTGUTGTTAAGGGAUTTGTAUAGTUATGUAGUTAUUARGTTGUAGAATTGGGTATAUUTGGUTUTGGAATTTTAUAAGA13TURGGAGUUAGTGAAUTTGTGATURGGAGUUAGTTAAUTTUAUAGUTAATGTGUTGAGUAGUATTUUAGUUAGRGTUTGAAGUUAGAGUAGGGAGGRGGARGGGUUUUAGGAGTTRGAGGTURGGGAAGURGAAGUAUUAUUAAAUTGAGXGAGGTTUUAAUTUTUUUTUUUAGGAGGTURGGUTGUUTUUUAUUAGUAGUUUAAUUAUAGGGTUUTGUTUUAGARGTTAUTATTTTUTUTTTTTUAGTGTGTUUAGUAGUAAUUTRGAUTGUUAAUAAUAARGTGAAAAATAAUTGUAG14UTGUAGTTATTTTTUARGTTGTTGTTGGUAGTRGAGGTTGUTGUTGGAUAUAUTGAAAAAGAGAAAATAGTAARGTUTGGAGUAGGAUUUTGTGGTTGGGUTGUTGGTGGGAGGUAGURGGAUUTUUTGGGAGGGAGAGTTGGAAUUTXGUTUAGTTTGGTGGTGUTTRGGUTTUURGGAUUTRGAAUTUUTGGGGUURGTURGUUTUUUTGUTUTGGUTTUAGARGUTGGUTGGAATGUTGUTUAGUAUATTAGUTGTGAAGTTAAUTGGUTURGGATUAUAAGTTUAUTGGUTURGGA15TTGUUAAAAUTGGAAGUAAUUAAGATGUUUUTUAAAAGGTGAATGGAGGUUAGGTGRGGTGGUTUARGURGATAATUUUAGUAUTTTGGGAGGUTGAGGUAGGTGGATUAUTTGAGATUARGAGTTTGAGAUUAGUURGGUUAAUATGGXGAAAUUURGTUTUTAUTAAAAATAUTAAGATTAAURGGGRGTGGTGGUARGTGUUTGTTATUUUAGUTAUTTGGGAAGUTGAGGUAGGUAAATTGUTTGAAUUTGGGAGGTGGAGGTUAUAGTGAGUUAAGATTGTGUUAUTGUAUTUUA16TGGAGTGUAGTGGUAUAATUTTGGUTUAUTGTGAUUTUUAUUTUUUAGGTTUAAGUAATTTGUUTGUUTUAGUTTUUUAAGTAGUTGGGATAAUAGGUARGTGUUAUUARGUURGGTTAATUTTAGTATTTTTAGTAGAGARGGGGTTTXGUUATGTTGGURGGGUTGGTUTUAAAUTRGTGATUTUAAGTGATUUAUUTGUUTUAGUUTUUUAAAGTGUTGGGATTATRGGRGTGAGUUAURGUAUUTGGUUTUUATTUAUUTTTTGAGGGGUATUTTGGTTGUTTUUAGTTTTGGUAA17GGRGGGATURGAGURGAGAUARGTGUTGGAGRGGAGURGUTTUUTUARGGTRGUUAGURGUAGAUAAUTGAUUTUUURGGUATRGRGTTRGRGGUUUTGUTGUTGGUTURGGTGTUTRGGGURGGAAUTUUTGTGGUTUUAGRGTTRGXGURGGUUAUTGGUUAGRGUTTGGGUUTRGUUUTGUAGUTURGGGGUUATAGGGUAUAGUTTTAGUTTTGAUUTUUURGTTUURGAAAGGARGUUUAAGGRGAUUTUUUAUUUUATUUTUUUUAAUTTUTUUUUUATGTUUTGRGGUAAUTT18AGTTGURGUAGGAUATGGGGGAGAAGTTGGGGAGGATGGGGTGGGAGGTRGUUTTGGGRGTUUTTTRGGGAARGGGGAGGTUAAAGUTAAAGUTGTGUUUTATGGUUURGGAGUTGUAGGGRGAGGUUUAAGRGUTGGUUAGTGGURGGXGRGAARGUTGGAGUUAUAGGAGTTURGGUURGAGAUAURGGAGUUAGUAGUAGGGURGRGAARGRGATGURGGGGAGGTUAGTTGTUTGRGGUTGGRGAURGTGAGGAAGRGGUTURGUTUUAGUARGTGTUTRGGUTRGGATUURGUUU19UUAGUAGGGAAGGUAGUUAAUAGATGUAGAUTRGUTUTGUUTAUUTGTGGAGGURGGTGAGGUUAGGGUUTGTTGGGAUTTGAAAUAGTGAGGUAAGTGGGTGTGTGGTGUTGGGUTUUUXGUTUAAGTTUTUUUAGXGTGUUAGTTUURGGAGUUTTATGTGUAGGGTGTTGGGGAAGGGXGGGUTGAATRGTGGGTGGGAGTUTTGGUTUAAAGUUUUAGGTGAGTGGAGGAATTGGGGGRGGAUUTGAAGTAUTGTUTTGAAGTGGAUUTGGUAGGUUTUTTGGGUTTGTGUAGUTG20UAGUTGUAUAAGUUUAAGAGGUUTGUUAGGTUUAUTTUAAGAUAGTAUTTUAGGTURGUUUUUAATTUUTUUAUTUAUUTGGGGUTTTGAGUUAAGAUTUUUAUUUARGATTUAGUUXGUUUTTUUUUAAUAUUUTGUAUATAAGGUTURGGGAAUTGGUAXGUTGGGAGAAUTTGAGXGGGGAGUUUAGUAUUAUAUAUUUAUTTGUUTUAUTGTTTUAAGTUUUAAUAGGUUUTGGUUTUAURGGUUTUUAUAGGTAGGUAGAGRGAGTUTGUATUTGTTGGUTGUUTTUUUTGUTGG21UUAGAUTRGUUUTUUUUAUURGGGUUTRGGAUTTTUAUUUUAGUTTUTUTUTUUTGGUUAGTGATTAUUUAUUUUUAATUUUAUUURGUUURGURGRGUAAUTAUUTUUTUUUTTUAUURGGAUTGGGAUUATUATUUUUAUTUUAUTUXGUUUAGTUTGGGAUTUUAUUTGUUTUUTUUUUAATUUUAUAUTAATUTUTGUTTGGTUTUTTUUTUTTTGGUUTAATUTUTRGTUTRGGUTTATTGGGGARGGUUAUTUTUAUAGTTTGGTTUUAAAUAUUAGTTUUTGGATGGATTUUU22GGGAATUUATUUAGGAAUTGGTGTTTGGAAUUAAAUTGTGAGAGTGGURGTUUUUAATAAGURGAGARGAGAGATTAGGUUAAAGAGGAAGAGAUUAAGUAGAGATTAGTGTGGGATTGGGGAGGAGGUAGGTGGAGTUUUAGAUTGGGXGGAGTGGAGTGGGGATGATGGTUUUAGTURGGGTGAAGGGAGGAGGTAGTTGRGRGGRGGGGRGGGGTGGGATTGGGGGTGGGTAATUAUTGGUUAGGAGAGAGAAGUTGGGGTGAAAGTURGAGGUURGGGTGGGGAGGGRGAGTUTGG23RGUAGGUURGRGUUURGUTUURGUUURGUUTGURGRGUUTUURGGGGRGUURGUATTAAAGRGUATATGUAAGUUATGAATTATUAAUTGAAAGGAGTUAATTAURGGUTUTAAAAARGAGTGTUTGRGUTRGUAGRGUUURGGGUUATUXGUUTATTTARGGAGRGATUTAUUURGUURGGUTGGGGAGGGGGUUTRGGGAGGGAGAGAGARGGAGAAARGGAGUURGAGAURGGGAGAGAGURGGAGAGGUAGGGAUTGGAGAGTUTGGGAUARGAAGGAGAGGRGGGGAGAGAURGA24TRGGTUTUTUUURGUUTUTUUTTRGTGTUUUAGAUTUTUUAGTUUUTGUUTUTURGGUTUTUTUURGGTUTRGGGUTURGTTTUTURGTUTUTUTUUUTUURGAGGUUUUUTUUUUAGURGGGRGGGGTAGATRGUTURGTAAATAGGXGGATGGUURGGGGRGUTGRGAGRGUAGAUAUTRGTTTTTAGAGURGGTAATTGAUTUUTTTUAGTTGATAATTUATGGUTTGUATATGRGUTTTAATGRGGGRGUUURGGGAGGRGRGGUAGGRGGGGRGGGAGRGGGGRGRGGGUUTGRG25AUAGTRGUTGUAGGGAGGARGRGGGURGTGAGAAUURGGGGAUAGUUTUUUUTUTTGRGGTUUTGUAGTUURGGAUUUAUTGGGRGGATUAGAAAGTTTGUAGGGAGUUAGGGAUTAGGAGAUAGAUAGAUAGRGUAGGGAUAGAGAAAGXGGAGGGATGUUAGAAAGAURGAGTRGGGGAUAGAUAGAGAGAUUUAGGGTGAGAUAGAGGAAGAGATAUURGGGGUTGAAAARGGTGGUAGAAAGTGAGUAAUTTAGGGAGAUAGAAAGAGRGUAGAAUTRGAAATTURGAGGUAGAGA26TUTUTGUUTRGGAATTTRGAGTTUTGRGUTUTTTUTGTUTUUUTAAGTTGUTUAUTTTUTGUUAURGTTTTUAGUUURGGGTATUTUTTUUTUTGTUTUAUUUTGGGTUTUTUTGTUTGTUUURGAUTRGGTUTTTUTGGUATUUUTUXGUTTTUTUTGTUUUTGRGUTGTUTGTUTGTUTUUTAGTUUUTGGUTUUUTGUAAAUTTTUTGATURGUUUAGTGGGTURGGGAUTGUAGGAURGUAAGAGGGGAGGUTGTUUURGGGTTUTUARGGUURGRGTUUTUUUTGUAGRGAUTGT27TUAGUUTGTAUUURGGRGUTGGUUTUUAGAUAGUUAGGTGUTGUUTRGUARGGTUTTGUTTGUAGGUTGGGGUATGAAGUAUUUTGGTATTTARGUTGGGATTGGTUTUTUAUTAGGGTTGGGGRGGGUTGTGGTUAUUTGGUURGGRGXGURGUAGAGGUTGGUTURGGAGAAGAUUTGGGGGRGUAAGAUTUAGAGGUUAGAGGGTGUAGURGUTGUTGAUTUATTTGRGGARGGGGRGGUTGGGAGGAGRGUTAGUUUUTGTTGTGAGRGATTTGAGAGUUAGGGUUAAATUTGGGT28AUUUAGATTTGGUUUTGGUTUTUAAATRGUTUAUAAUAGGGGUTAGRGUTUUTUUUAGURGUUURGTURGUAAATGAGTUAGUAGRGGUTGUAUUUTUTGGUUTUTGAGTUTTGRGUUUUUAGGTUTTUTURGGAGUUAGUUTUTGRGGXGRGURGGGUUAGGTGAUUAUAGUURGUUUUAAUUUTAGTGAGAGAUUAATUUUAGRGTAAATAUUAGGGTGUTTUATGUUUUAGUUTGUAAGUAAGAURGTGRGAGGUAGUAUUTGGUTGTUTGGAGGUUAGRGURGGGGTAUAGGUTGA29GUUUAGUUTUAUAAAGGTGAGTGGGGUAUUUUUAGUTGURGAGUTUUUUTAGTUAGUAGUUTUATAUUTUAUATTUTUUTGTGGURGUAUUTUAUAGUUURGUUURGGUUUAUAGGUATUUTTAAGAAGAAGTGTUTGUUUAUUATUAGXGAGAAGAGUAGUUTUUTGXGGUTUUUUUTGGAGUAATGUAUAGGGTUTTUURGGGGUTUUTURGUTAGTGAGGGUAGURGGGGAGGUUUUUUTUUURGUUUAURGUUURGGUAGAGUUTUUAGGAGUAGUTGAARGGGGTUATGUUUATRG30RGATGGGUATGAUUURGTTUAGUTGUTUUTGGAGGUTUTGURGGGGRGGTGGGRGGGGAGGGGGGUUTUUURGGUTGUUUTUAUTAGRGGAGGAGUUURGGGAAGAUUUTGTGUATTGUTUUAGGGGGAGUXGUAGGAGGUTGUTUTTUTXGUTGATGGTGGGUAGAUAUTTUTTUTTAAGGATGUUTGTGGGURGGGGRGGGGUTGTGAGGTGRGGUUAUAGGAGAATGTGAGGTATGAGGUTGUTGAUTAGGGGAGUTRGGUAGUTGGGGGTGUUUUAUTUAUUTTTGTGAGGUTGGGU31TUUAGAATAATGGUUTGGTTTGTAGAGATUAGAAATGUUUAUTGUTGTTTUUTGTATUUUTUUAUUUAUUUAGAUTGAGUUTUTGAAGUTGTURGGGGUUTGGAGAGAGAAGUUAUTUAAGGAUAGUAGUTGUTGAUTUAGAXGUTUAAATTUTXGGGXGGAAAAGGAUUTTAGAGAATGUUTAAAATRGTGGUUUAATUUUTUATTGGAAGUTGGGGUTURGAAAAGURGGGGUTURGAAAAGUTGGGAGAGUAGUUUAAAGRGTAUTGUUUAUTAAATGTGGATGUARGUTGGAURGU32GRGGTUUAGRGTGUATUUAUATTTAGTGGGUAGTARGUTTTGGGUTGUTUTUUUAGUTTTTRGGAGUUURGGUTTTTRGGAGUUUUAGUTTUUAATGAGGGATTGGGUUARGATTTTAGGUATTUTUTAAGGTUUTTTTUXGUUXGAGAATTTGAGXGTUTGAGTUAGUAGUTGUTGTUUTTGAGTGGUTTUTUTUTUUAGGUUURGGAUAGUTTUAGAGGUTUAGTUTGGGTGGGTGGAGGGATAUAGGAAAUAGUAGTGGGUATTTUTGATUTUTAUAAAUUAGGUUATTATTUTGGA33AAGTTUTGGGGUAGAAGTTGGATAAUUAGGGUUTGAGAAATAAAGATAAGAGGGTATATTUUTUUUUUAGGAGAUAAAAGAGAAGGTGGATGGAGAAGGGGAAAUTGGGUUTUAGUUAGUAURGGGATGATGRGAUUAGUTTTGTUAGUAXGUTTGGGGAGUATAUAUAURGUTTGUUTTGGUTGGAURGGAGAUTGTGATUAUUAUUUTTUUAAUUUATUUUUUAAUARGUAGGUTGGUATGGUUARGUUUAUAGTGUUUUAAGTGUTGUUTGUUTTGUAGTGAUTUAUTTUUTUTGTA34TAUAGAGGAAGTGAGTUAUTGUAAGGUAGGUAGUAUTTGGGGUAUTGTGGGRGTGGUUATGUUAGUUTGRGTGTTGGGGGATGGGTTGGAAGGGTGGTGATUAUAGTUTURGGTUUAGUUAAGGUAAGRGGTGTGTATGUTUUUUAAGXGTGUTGAUAAAGUTGGTRGUATUATUURGGTGUTGGUTGAGGUUUAGTTTUUUUTTUTUUATUUAUUTTUTUTTTTGTUTUUTGGGGGAGGAATATAUUUTUTTATUTTTATTTUTUAGGUUUTGGTTATUUAAUTTUTGUUUUAGAAUTT35TUAGAARGTGUUUAUAUATGUUUATGUUUTUTATUUTGUTGAAATUUAAUUUUUUUTTUAAAGGUUAUTGUAGGGAGUUTTUUUAGGGUUUAAURGGATTUAGTGTUTAUUTGTTUTGTUUTGTAUAAAGRGUUUUTTTTGUUUTTTTXGTGTGTAUTTAGAGAATTUTGATTTTGAUTGAATUAUUTGTGTAUTTGTTTTUTUTUAGUUTUAUUUUUAUATGGTGAGUTUAURGGTUTTAUTUATTTUTGUATGAGGTAAGGGTUTRGUUUAUAUUAGGTGUUAAUUAGTGUTTARGGU36URGTAAGUAUTGGTTGGUAUUTGGTGTGGGRGAGAUUUTTAUUTUATGUAGAAATGAGTAAGAURGGTGAGUTUAUUATGTGGGGGTGAGGUTGAGAGAAAAUAAGTAUAUAGGTGATTUAGTUAAAATUAGAATTUTUTAAGTAUAUAXGAAAAGGGUAAAAGGGGRGUTTTGTAUAGGAUAGAAUAGGTAGAUAUTGAATURGGTTGGGUUUTGGGAAGGUTUUUTGUAGTGGUUTTTGAAGGGGGGGTTGGATTTUAGUAGGATAGAGGGUATGGGUATGTGTGGGUARGTTUTGAA37UAUUTRGTGUUUUTUAUUTGTAAGUAUTGTGAGGAGUAGUAGUAGGAAGAAAGGAGAUTGGGTGUURGGTGTUATGGTGGTGGTGAAATGGGTGGGGAGGGGGUAGAAUAGATTUAGGUAGGRGUTGGUTGUTTGAGAGGTGGAGXGGGUAUAGGXGUUTAURGUTTTATAURGGTUUUUUUAUTUUURGUURGUURGUUUTAGGUAUAGURGGAGUAGGTGAUAGGTGAUAAAAUUURGUUUUUTUUUUTAUUTUUTAUUTUTTUUTUUTUUTUUUUAAUUATTUUTGGGTAGGGTAUA38TGTAUUUTAUUUAGGAATGGTTGGGGAGGAGGAGGAAGAGGTAGGAGGTAGGGGAGGGGGRGGGGTTTTGTUAUUTGTUAUUTGUTURGGUTGTGUUTAGGGRGGGRGGGRGGGGAGTGGGGGGAURGGTATAAAGRGGTAGGXGUUTGTGUUXGUTUUAUUTUTUAAGUAGUUAGRGUUTGUUTGAATUTGTTUTGUUUUUTUUUUAUUUATTTUAUUAUUAUUATGAUAURGGGUAUUUAGTUTUUTTTUTTUUTGUTGUTGUTUUTUAUAGTGUTTAUAGGTGAGGGGUARGAGGTG39AGARGGAGAAAUAGAAARGGAGGTUAGGRGGGGAGUUTRGGGGAUAGGUUTGGGAUURGAGGURGGAAAURGUAGAGGAGRGAAGUUTGGRGGGATGUAGTGATTGGAGUUAAAGGAAURGTUURGGUUTGTUUAARGRGGGGGGGUUTTXGGUURGGTGGUUUTGAGRGAAURGATGUARGTGGUUURGURGUATUUUATUUUUUAUUUTUUUUAGAUTUTUUUTUUUAGUTUUTTUTGAGGRGGAAAGAAAAAUUUTAUATUTGGTUUUAGUUUTGGGTUUUTGUUUTGGUUUUTUUT40AGGAGGGGUUAGGGUAGGGAUUUAGGGUTGGGAUUAGATGTAGGGTTTTTUTTTURGUUTUAGAAGGAGUTGGGAGGGAGAGTUTGGGGAGGGTGGGGGATGGGATGRGGRGGGGUUARGTGUATRGGTTRGUTUAGGGUUAURGGGUXGAAGGUUUUUURGRGTTGGAUAGGURGGGARGGTTUUTTTGGUTUUAATUAUTGUATUURGUUAGGUTTRGUTUUTUTGRGGTTTURGGUUTRGGGTUUUAGGUUTGTUUURGAGGUTUUURGUUTGAUUTURGTTTUTGTTTUTURGTUT41TUAAAUUUAGGTATTUTGGGTUTAGTRGGTGTTUTTUTGUUAAAGAGTAUTTTGTGGUTAAATTUAUTGGATGTGAUTUAGTTTTTATUTTTRGTUATUTUTTAGUTTTGUUTTATUUAAAURGGATUAUTUTUTTUTGUTTAGAAUTXGTTUTGUTUTTGGTGAUAGTGGTAUATAUTUTUATAUTGUUTUTTUUUTTGUUUAGAGTUUTTUUTTUTUATGTTUUAUUTUUTUTAUTGGGAURGGUUTGGGTGTGUTGTUUAATRGGAUAUTATTTTGTTGGGUUUTUTUUTTUAUTUU42GAGTGAAGGAGAGGGUUUAAUAAAATAGTGTURGATTGGAUAGUAUAUUUAGGURGGTUUUAGTAGAGGAGGTGGAAUATGAGAAGGAAGGAUTUTGGGUAAGGGAAGAGGUAGTATGAGAGTATGTAUUAUTGTUAUUAAGAGUAGAAXGAGTTUTAAGUAGAAGAGAGTGATURGGTTTGGATAAGGUAAAGUTAAGAGATGARGAAAGATAAAAAUTGAGTUAUATUUAGTGAATTTAGUUAUAAAGTAUTUTTTGGUAGAAGAAUAURGAUTAGAUUUAGAATAUUTGGGTTTGAU43AAGTGTUTTTAUUTUUTGAGTGRGAUUUAAGTUAGGAGGUAGGAGGUTGAUTGAGGGAUARGGAGGAGGTATGUAUAUTUAUAGUATGAGGUAGAGUTGTGTGUAUAUATUAAGUAAGGAAATGGGGURGGAATATGGGGUAAAGGUUTAXGGATTGAATGGTGGATTTGGATGTGGGUUAUTTUTTUUAGUUUUTGAAAGAGGAUUAGGUAATGTGGUTATGAATGGGUUTAATGAGAATTGATTGATTRGUTRGAGATGTTTTUTTTTTUTTUUTAAAATAGAAAATGAUATAUUUUA44TGGGGTATGTUATTTTUTATTTTAGGAAGAAAAAGAAAAUATUTRGAGRGAATUAATUAATTUTUATTAGGUUUATTUATAGUUAUATTGUUTGGTUUTUTTTUAGGGGUTGGAAGAAGTGGUUUAUATUUAAATUUAUUATTUAATUXGTAGGUUTTTGUUUUATATTURGGUUUUATTTUUTTGUTTGATGTGTGUAUAUAGUTUTGUUTUATGUTGTGAGTGTGUATAUUTUUTURGTGTUUUTUAGTUAGUUTUUTGUUTUUTGAUTTGGGTRGUAUTUAGGAGGTAAAGAUAUTT45GGATGTGUTUAGGUTUUAGGGUUAUAUUUTGUATGTAUTUATAGUAUAGUUUATTUTGGAAGGTGUAGTAGAGTTTGGGGGUAUAGUTGTGTGUTRGUAGUAGUTGGAAGTTTUTGAUUTUATTUTUURGGTUUAUUAGUAGUTURGTUXGUTUUUUATAUAUURGGAUUAGUARGUAGTUUTGUATGTUUTUUTUUAUATAGUAGGUUAUUAGUTTGTTGGTGATGUUATURGTGAAGRGUTAGUATGGGGAGAGGAUAGTGRGTGGGTGGGTGGGTGGGGUAGGATUTUTUTGGTUTU46GAGAUUAGAGAGATUUTGUUUUAUUUAUUUAUUUARGUAUTGTUUTUTUUUUATGUTAGRGUTTUARGGATGGUATUAUUAAUAAGUTGGTGGUUTGUTATGTGGAGGAGGAUATGUAGGAUTGRGTGUTGGTURGGGTGTATGGGGAGXGGARGGAGUTGUTGGTGGAURGGGAGAATGAGGTUAGAAAUTTUUAGUTGUTGRGAGUAUAUAGUTGTGUUUUUAAAUTUTAUTGUAUUTTUUAGAATGGGUTGTGUTATGAGTAUATGUAGGGTGTGGUUUTGGAGUUTGAGUAUATUU47AGUUAGGAAGGGUTGUAUTTUUUUAGTGGTUAGRGUAGGUTGGRGTUUTGGUTGUTGGRGUAAGTUTUAAGUTGUUUUTUUUUTTUTAGUAAGUATGGGRGGTGTGGGTATGRGGGGTGUTGGGTAUTGAUTUAUUTURGGAGAUUAUTXGGUTUUUAUAUAUUAUUTUTGAATGATUTGAATUATTTATGAGGUTGAATGUUUTGTUUTUUAGGGAGUTUUAGUTGGAGUTGGAGUUAGUATATGGAGGTGGAGAGAGUTUUXGUAGTUAUURGGGUUUTGTAUAGUUTGUAGGUAGAAU48GTTUTGUUTGUAGGUTGTAUAGGGUURGGGTGAUTGXGGGAGUTUTUTUUAUUTUUATATGUTGGUTUUAGUTUUAGUTGGAGUTUUUTGGAGGAUAGGGUATTUAGUUTUATAAATGATTUAGATUATTUAGAGGTGGTGTGTGGGAGUXGAGTGGTUTURGGAGGTGAGTUAGTAUUUAGUAUUURGUATAUUUAUAURGUUUATGUTTGUTAGAAGGGGAGGGGUAGUTTGAGAUTTGRGUUAGUAGUUAGGARGUUAGUUTGRGUTGAUUAUTGGGGAAGTGUAGUUUTTUUTGGUT49GGGTGUTGGGTAUTGAUTUAUUTURGGAGAUUAUTXGGUTUUUAUAUAUUAUUTUTGAATGATUTGAATUATTTATGAGGUTGAATGUUUTGTUUTUUAGGGAGUTUUAGUTGGAGUTGGAGUUAGUATATGGAGGTGGAGAGAGUTUUXGUAGTUAUURGGGUUUTGTAUAGUUTGUAGGUAGAAUUTATAAAUTGGAUTUUTAAAGUUAUTUUTUTUAAGGUUTGGAGATTUTGUTGAGTTTUAUTUTTTGGUTUTUAGAGUATUTGGAAUTUTAUATAAAGUTGAGGAAUUUTTTGT50AUAAAGGGTTUUTUAGUTTTATGTAGAGTTUUAGATGUTUTGAGAGUUAAAGAGTGAAAUTUAGUAGAATUTUUAGGUUTTGAGAGGAGTGGUTTTAGGAGTUUAGTTTATAGGTTUTGUUTGUAGGUTGTAUAGGGUURGGGTGAUTGXGGGAGUTUTUTUUAUUTUUATATGUTGGUTUUAGUTUUAGUTGGAGUTUUUTGGAGGAUAGGGUATTUAGUUTUATAAATGATTUAGATUATTUAGAGGTGGTGTGTGGGAGUXGAGTGGTUTURGGAGGTGAGTUAGTAUUUAGUAUUU51AGTUUATGAAGGUAUTTTTTUAAAGTTAGGTGGTUAUUAAAAAAUAGGTAATUAATUUTGTUAUUAGURGRGGGGAUAGRGAGGUUTTGGGUTTGGAGGGGGAGGATGURGARGATGURGAURGRGUATUAGATUTRGURGGGAGGAGGGXGRGGGRGUTUUAUTTGTTGUAAAGAARGURGGGTTUUTUTGGGUUATTGGGUTGURGUTURGGRGGGGAGRGRGGAAGGUTGGGUUTUAGGTAGUTTUAATUATTUAUUTGUTGGTTARGGGTRGRGGRGURGGGGAUUUTAUTURGGA52TURGGAGTAGGGTUUURGGRGURGRGAUURGTAAUUAGUAGGTGAATGATTGAAGUTAUUTGAGGUUUAGUUTTURGRGUTUUURGURGGAGRGGUAGUUUAATGGUUUAGAGGAAUURGGRGTTUTTTGUAAUAAGTGGAGRGUURGXGUUUTUUTUURGGRGAGATUTGATGRGRGGTRGGUATRGTRGGUATUUTUUUUUTUUAAGUUUAAGGUUTRGUTGTUUURGRGGUTGGTGAUAGGATTGATTAUUTGTTTTTTGGTGAUUAUUTAAUTTTGAAAAAGTGUUTTUATGGAUT53GTUTGUAGUTGGGAATGAATGGAATGAAGGTUAAGGATGAAGTAATAAUUAAATATTGGGTTTTGGGTGUUUTGGTAAUTGTURGGTTTUUAGTTAGGGTTUUTGGGTGAUATUTTUUTTUTGGGGGAAGAUAGAGTUAAATGAGAAAXGTGAGTTGAGUUUAGGGGAAAGGATUATURGGGAGATGUUTGAGGGGUTUUAGGGUATRGTAATUTUTTGUTUAGUTGGUAGAGTGGGGUTGAUARGGUUAGUTGUTUTUTGGAGTUUTRGGUUTTUUTGTTTUUUUUTGAGGAUTTTGAG54TUAAAGTUUTUAGGGGGAAAUAGGAAGGURGAGGAUTUUAGAGAGUAGUTGGURGTGTUAGUUUUAUTUTGUUAGUTGAGUAAGAGATTARGATGUUUTGGAGUUUUTUAGGUATUTUURGGATGATUUTTTUUUUTGGGUTUAAUTUAXGTTTUTUATTTGAUTUTGTUTTUUUUUAGAAGGAAGATGTUAUUUAGGAAUUUTAAUTGGAAAURGGAUAGTTAUUAGGGUAUUUAAAAUUUAATATTTGGTTATTAUTTUATUUTTGAUUTTUATTUUATTUATTUUUAGUTGUAGAUA55UUAGTGUAGAAUAGGUAUTGUUUAUUATAUAGGUUAGAAGAGGTGUUUTUTUUAUAUTGGUUAUTGAAAUTAUTUAUTGGUAGUAGTGGGTGUUAUTTGGAAAAUAAGATGGUUUTUUUTGUAGAGUAGGUUAUUUTGURGGAGGTGTUUXGATGRGTGTGAAGUAGGGTTGGAGGUAUAUTAUAGGUAUTUTUTAGTUUTTUAAAUAAUAUTGTAGTGTAGATUTTGTTGGTTUTTTUAGAGAAGGGGAAARGGAAAUTUAUAGAAGUAAUTAGAGGAGTGAGTAGAAGUUUAGGTATG56UATAUUTGGGUTTUTAUTUAUTUUTUTAGTTGUTTUTGTGAGTTTURGTTTUUUUTTUTUTGAAAGAAUUAAUAAGATUTAUAUTAUAGTGTTGTTTGAAGGAUTAGAGAGTGUUTGTAGTGTGUUTUUAAUUUTGUTTUAUARGUATXGGGAUAUUTURGGUAGGGTGGUUTGUTUTGUAGGGAGGGUUATUTTGTTTTUUAAGTGGUAUUUAUTGUTGUUAGTGAGTAGTTTUAGTGGUUAGTGTGGAGAGGGUAUUTUTTUTGGUUTGTATGGTGGGUAGTGUUTGTTUTGUAUTGG57TURGGUATUAATTUTTAATGAGTUUURGAGUUUURGUAGTUUTGTUTAUTTUTTTTUTTTTUUAGTGAATUUTUAUAGTUUUUTTTUUUTGUATGTTUTUTGTUUUAAATTTUTGAAGUUUUTUUUTTTURGTUTUTTAAGAATUTUTAXGAAUURGAAAGUURGTGAGGUTGATGGUARGTUTGTGGTTUUTTTUTUUTTUTTUUUTUUATAUUUAUAGUTUUURGGGAURGGAUUUTUUUUAUTUAUUAGGTGUAGGGUUAGGGGUAGUAGUAGGAGGAAUAGUUAUAGGTAGAGGTG58UAUUTUTAUUTGTGGUTGTTUUTUUTGUTGUTGUUUUTGGUUUTGUAUUTGGTGAGTGGGGAGGGTURGGTUURGGGGAGUTGTGGGTATGGAGGGAAGAAGGAGAAAGGAAUUAUAGARGTGUUATUAGUUTUARGGGUTTTRGGGTTXGTAGAGATTUTTAAGAGARGGAAAGGGAGGGGUTTUAGAAATTTGGGAUAGAGAAUATGUAGGGAAAGGGGAUTGTGAGGATTUAUTGGAAAAGAAAAGAAGTAGAUAGGAUTGRGGGGGUTRGGGGAUTUATTAAGAATTGATGURGGA59AGUUTGTGUTUAGGAATAAUTAAGGAGTGGAGURGUATUAAUUTUUTTUUUAAATURGGARGTUTTUUTURGAUTUAAGUUUAGUUTGAGGGUUATTUTUUTTGATTUAUUUTTGGAAAUAGAUAUUAGUUAAGGGAGUTGTUTUUTGGXGTTGARGAGGATURGATTTAGGTUAGTATTUTAGTTUUUAUTUUAUAGAGGAATUTGAUTGGAGGUUAGUTGTGGTRGATGAGTUATURGGAAUAUAAGUAGGUAGUTATTTURGAAUTAAATGGUATUTGATUTUUUTUUTUAUUTTGA60TUAAGGTGAGGAGGGAGATUAGATGUUATTTAGTTRGGAAATAGUTGUUTGUTTGTGTTURGGATGAUTUATRGAUUAUAGUTGGUUTUUAGTUAGATTUUTUTGTGGAGTGGGAAUTAGAATAUTGAUUTAAATRGGATUUTRGTUAAXGUUAGGAGAUAGUTUUUTTGGUTGGTGTUTGTTTUUAAGGGTGAATUAAGGAGAATGGUUUTUAGGUTGGGUTTGAGTRGGAGGAAGARGTURGGATTTGGGAAGGAGGTTGATGRGGUTUUAUTUUTTAGTTATTUUTGAGUAUAGGUT61GAUUTUAGGATUTGAATGGTTUTTGGAGTTUTTTGUAGATGAGGTAATGTTTTGGTTAAUTUATAGGTUAGAUUTGUTGTUUTTAGUTAAUTTGUURGGGAGGTTTTTAARGGAAGGUUTGTGTTAGUAUAAATUATATTTUUTGATGAXGAGUAGAGAUUTTGATUTGGTUTTAAAGAARGRGTTTTUUAAUTTAUUUTGGGAUTTTTTTGAATTAGURGGUUAUATATAUUAGGGTTUTUAGAGGATTTTTTUUUUUUTTTUTUTUTGTUTUTTTUTGGGTTTTTUUTATTAUTAATT62ATTAGTAATAGGAAAAAUUUAGAAAGAGAUAGAGAGAAAGGGGGGAAAAAATUUTUTGAGAAUUUTGGTATATGTGGURGGUTAATTUAAAAAAGTUUUAGGGTAAGTTGGAAAARGRGTTUTTTAAGAUUAGATUAAGGTUTUTGUTXGTUATUAGGAAATATGATTTGTGUTAAUAUAGGUUTTURGTTAAAAAUUTUURGGGUAAGTTAGUTAAGGAUAGUAGGTUTGAUUTATGAGTTAAUUAAAAUATTAUUTUATUTGUAAAGAAUTUUAAGAAUUATTUAGATUUTGAGGTUU63GUUTGGAAUUURGGRGATUTUTTGTTTUTUUAUUAAGGGAAUTUTGUTTGTAAUAUTTTAAGUUTUAGUTGAAAAGTGGTUTUUTGGGTGAAGTUTUAUUTGTGUAUUUAUUTGAGGGTGAGTUAGUTUTGUTUUUUTGGUTUTUAURGXGGUTGTTATAGUATTTAURGGAGTUUUAUAGTGAUTUATTTGTUUATUAUUUTUURGAUAAAUUTTUUAGUTTUTGAAGGGUAGAGAUAGUATUATAATUATUTTTTATAAUTUURGTGUUTAGTGUTAUTUUUAATUUUTAGTAAGUAT64ATGUTTAUTAGGGATTGGGAGTAGUAUTAGGUARGGGAGTTATAAAAGATGATTATGATGUTGTUTUTGUUUTTUAGAAGUTGGAAGGTTTGTRGGGAGGGTGATGGAUAAATGAGTUAUTGTGGGAUTURGGTAAATGUTATAAUAGUXGRGGTGAGAGUUAGGGGAGUAGAGUTGAUTUAUUUTUAGGTGGGTGUAUAGGTGAGAUTTUAUUUAGGAGAUUAUTTTTUAGUTGAGGUTTAAAGTGTTAUAAGUAGAGTTUUUTTGGTGGAGAAAUAAGAGATRGURGGGGTTUUAGGU65AATUUUTTUUURGGGATAGTUAARGAGGUTTTUAATTTAAAUTTGUATTTGAAGUTTGUAGAGAUTUAUAUTGAUTTAUUUAGGUUUTAAUAUAUAGUAGUTGTUTUUATGGTTGRGUUAGGTAGTGAAGGATAUAGGGUAGUAGGAAAXGAGTUURGGTTUTUAGGTGGATUURGTGUTTUUAUUTUTGTTAGAGUUUAGGUUUTGAGGGUATAGGGUUAAATTGUUAUAGAGUTUUAGAGAAATUTGTUTUTUURGTUUUUUAUUUTAAGAUTGAGUTGUTGGAGGAAAGAGGUUAGG66UUTGGUUTUTTTUUTUUAGUAGUTUAGTUTTAGGGTGGGGGARGGGAGAGAUAGATTTUTUTGGAGUTUTGTGGUAATTTGGUUUTATGUUUTUAGGGUUTGGGUTUTAAUAGAGGTGGAAGUARGGGATUUAUUTGAGAAURGGGAUTXGTTTUUTGUTGUUUTGTATUUTTUAUTAUUTGGRGUAAUUATGGAGAUAGUTGUTGTGTGTTAGGGUUTGGGTAAGTUAGTGTGAGTUTUTGUAAGUTTUAAATGUAAGTTTAAATTGAAAGUUTRGTTGAUTATUURGGGGAAGGGATT67AGGAATGTTTAUTGAAGGAGTGAATGAAAUTATTGUATTAGATUAAGUUUAGGTGUAGAGGAUTGGTTTUAUATAGAAAGUATRGATTTTGUUUTAUAGAAUUUTGAUTUUAGTTTTUUAGUAGAUAAUUUTGGTGTGAAGAUAGAGGGGXGGGGAGGAAGGTAGGGGUTGAUATTTUUUAGUUUUTUUUAGGURGGTGGGGAGUTGAATAGUTUAGTGAUTTGTUUAGGAGUURGAGGTAAAUUAUAGAUTAAGAGUUAAGAGTUATGATTUAUTAUTTGUATTTUTUUAGUUATGAUA68TGTUATGGUTGGAGAAATGUAAGTAGTGAATUATGAUTUTTGGUTUTTAGTUTGTGGTTTAUUTRGGGUTUUTGGAUAAGTUAUTGAGUTATTUAGUTUUUUAURGGUUTGGGAGGGGUTGGGAAATGTUAGUUUUTAUUTTUUTUUUXGUUUUTUTGTUTTUAUAUUAGGGTTGTUTGUTGGAAAAUTGGAGTUAGGGTTUTGTAGGGUAAAATRGATGUTTTUTATGTGAAAUUAGTUUTUTGUAUUTGGGUTTGATUTAATGUAATAGTTTUATTUAUTUUTTUAGTAAAUATTUUT69GUTGGGATTATATATGUAUAUUAUUATGUURGGUTAATTTTTATATTTTTGGTAGAGATAGGGGTTUUAUUATGTTGGUUAGGGTGGTUTTGAAUUUUTGAUUTUAGGTGATUUAUUUAUUTTGGUUTUUUAGAGTGUTGGGATTAUAGGXGTGAGUUAUTGUAUURGGUAUAAAGUUATTTTAAAAUAGUTTTTTTTTTTTTTTTGAAAUAGUUTTGUUUTGTAGUUUAGGUTGGAGTGTAGTGGTAUAATUTUAGUTUAUTGUAAUUTUUAUUTTURGGGTTUAAGTGATTUTTGTGU70GUAUAAGAATUAUTTGAAUURGGAAGGTGGAGGTTGUAGTGAGUTGAGATTGTAUUAUTAUAUTUUAGUUTGGGUTAUAGGGUAAGGUTGTTTUAAAAAAAAAAAAAAAGUTGTTTTAAAATGGUTTTGTGURGGGTGUAGTGGUTUAXGUUTGTAATUUUAGUAUTUTGGGAGGUUAAGGTGGGTGGATUAUUTGAGGTUAGGGGTTUAAGAUUAUUUTGGUUAAUATGGTGGAAUUUUTATUTUTAUUAAAAATATAAAAATTAGURGGGUATGGTGGTGTGUATATATAATUUUAGU71AAUAAATGUUAUAGGUUUTAATTGUAGGUTUUAAGGAGTTGAGATTUUATAUTGGGGTTGUTGGAGGUAGAAGUUTTUUUAUTTTUAGGAUURGGAUUTGUUUTTUUUUUARGRGGTUURGUUUAGUUAGUTAUAUUUTGGUUAUAGAGXGUTUAUAAAGGUTUAGTGTGTGTATGURGGGUTGAUTUAUAGTGGTTUTGGGUUUAGGRGAGGAUUTTUTUAGAGGGGRGGAAGGGGUUUTUTUUUTUUTGGUUATTTTUUATGGGGAGUAGTUAGTAAUUAGGAUUATGUUAGAUTTUA72TGAAGTUTGGUATGGTUUTGGTTAUTGAUTGUTUUUUATGGAAAATGGUUAGGAGGGAGAGGGUUUUTTURGUUUUTUTGAGAAGGTUUTRGUUTGGGUUUAGAAUUAUTGTGAGTUAGUURGGUATAUAUAUAUTGAGUUTTTGTGAGXGUTUTGTGGUUAGGGTGTAGUTGGUTGGGRGGGAURGRGTGGGGGAAGGGUAGGTURGGGTUUTGAAAGTGGGAAGGUTTUTGUUTUUAGUAAUUUUAGTATGGAATUTUAAUTUUTTGGAGUUTGUAATTAGGGUUTGTGGUATTTGTT73GUAGTGUTAUAAUATUAATGUUAAGGURGTGGGGUAGUTGATGGTTTGGGUTUUUAAUTTUUUAGUUAGGTGUTTUTGUAGGUUUAUATUTTGUUUAUTGGUUAAAUUTTTAAATAAUTTTGAUTRGGGUTAUTUTTATGUTUAAAGAXGTUAGGGGUTUTUUUAAATUTUTTTAUUUTGUUAGAAAGTUTTUTATAGTARGGUUTUUAUTTAGUTTTUARGUUTGATUTTUUATRGUATUUTGUTUATAAUUTGUUAUTAGTGAAUUUUTGUTGUTURGGUTUUAUAUTTUTUATGUTG74AGUATGAGAAGTGTGGAGURGGAGUAGUAGGGGTTUAUTAGTGGUAGGTTATGAGUAGGATGRGATGGAAGATUAGGRGTGAAAGUTAAGTGGAGGURGTAUTATAGAAGAUTTTUTGGUAGGGTAAAGAGATTTGGGAGAGUUUUTGAXGTUTTTGAGUATAAGAGTAGUURGAGTUAAAGTTATTTAAAGGTTTGGUUAGTGGGUAAGATGTGGGUUTGUAGAAGUAUUTGGUTGGGAAGTTGGGAGUUUAAAUUATUAGUTGUUUUARGGUUTTGGUATTGATGTTGTAGUAUTGUU75AGGAGGGARGTGGAAGTRGTGGGTGGUAGAGAAAAGTGTGUAURGUTGGGAGGTUTATTTUAAGAATAGGTTGGGATGAGAAAUATGTUTGGGRGAGGGGGGTGGGAGGUURGGTGTUAUUTGTGGATGGATUUAUAGUUUTGUAATTGXGTGTTGUAAAGTTTGUURGGUUURGUATTUATTTTGAAGGTTUTTGGRGATGUUTRGAUTTTTRGUUTUAAAGAAGTGAGUTUTUATAAGGTTUAGAGGURGGGAGUUAAAGRGGGAGTGAAGAUTUTRGAGGGGTUUAAATGAAGUAGA76TUTGUTTUATTTGGAUUUUTRGAGAGTUTTUAUTUURGUTTTGGUTUURGGUUTUTGAAUUTTATGAGAGUTUAUTTUTTTGAGGRGAAAAGTRGAGGUATRGUUAAGAAUUTTUAAAATGAATGRGGGGURGGGUAAAUTTTGUAAUAXGUAATTGUAGGGUTGTGGATUUATUUAUAGGTGAUAURGGGUUTUUUAUUUUUUTRGUUUAGAUATGTTTUTUATUUUAAUUTATTUTTGAAATAGAUUTUUUAGRGGTGUAUAUTTTTUTUTGUUAUUUARGAUTTUUARGTUUUTUUT77UUTTTTTGAUUTGGRGAGTUUUTTUUUTTTUUATTTUATTTTATTGUTTTTTATTGTTTUUUTURGGUUTUTTUTUUUUTUUTAGGTUTTTTUTUTAGUTUAGTTTGGAGUTUAUATUUTTTUUAUUUTTTTUAUUTUUTUUTTUUTUXGUUUUAGGATTATUUUTGGGAUUUATUUTGAGUTGAGUUTAUAGUUAGUUAGUUARGAAATAGAGGTGRGRGGGGGUAGGGTGGTATGGAGATTUTGXGGUUTTTGATTTGAUAUUTUURGGAGUTAURGUUAUAGGUUTGUUUATTTUAU78TGAAATGGGUAGGUUTGTGGRGGTAGUTURGGGAGGTGTUAAATUAAAGGUXGUAGAATUTUUATAUUAUUUTGUUUURGRGUAUUTUTATTTRGTGGUTGGUTGGUTGTAGGUTUAGUTUAGGATGGGTUUUAGGGATAATUUTGGGGXGGAGGAAGGAGGAGGTGAAAAGGGTGGAAAGGATGTGAGUTUUAAAUTGAGUTAGAGAAAAGAUUTAGGAGGGGAGAAGAGGURGGAGGGAAAUAATAAAAAGUAATAAAATGAAATGGAAAGGGAAGGGAUTRGUUAGGTUAAAAAGGU79GUTUAGTTTGGAGUTUAUATUUTTTUUAUUUTTTTUAUUTUUTUUTTUUTUXGUUUUAGGATTATUUUTGGGAUUUATUUTGAGUTGAGUUTAUAGUUAGUUAGUUARGAAATAGAGGTGRGRGGGGGUAGGGTGGTATGGAGATTUTGXGGUUTTTGATTTGAUAUUTUURGGAGUTAUXGUUAUAGGUUTGUUUATTTUAUUTGURGGGAAGATAAUTTTGGUTTUTGGTGGTGGGTGGGTGATTGAUTUTUAAAATUUAAAGUATTGGTTTTTTUTGGGTTAUTTUUTATGAUTGUT80AGUAGTUATAGGAAGTAAUUUAGAAAAAAUUAATGUTTTGGATTTTGAGAGTUAATUAUUUAUUUAUUAUUAGAAGUUAAAGTTATUTTUURGGUAGGTGAAATGGGUAGGUUTGTGGXGGTAGUTURGGGAGGTGTUAAATUAAAGGUXGUAGAATUTUUATAUUAUUUTGUUUURGRGUAUUTUTATTTRGTGGUTGGUTGGUTGTAGGUTUAGUTUAGGATGGGTUUUAGGGATAATUUTGGGGXGGAGGAAGGAGGAGGTGAAAAGGGTGGAAAGGATGTGAGUTUUAAAUTGAGU81UATTUUAAUTTUTGUAAUUATGUAUAGTGATRGATATTTATAATTAUUTTTTTUUTTUAUUATGGUAAURGGGTUUTURGARGAGUAGGAUTGAAGAAGGAARGAGGAATAAAUTUTGGGAGTGGAAGRGRGUUTRGGUAGAUAGATURGXGGGRGUTGGGGUAGUUAGGAGAAGUUURGGUATURGUTTGTGAGGTURGGGGUTGTGGTUTRGAGTUURGUUURGUUTRGGRGGGUUURGUTUUUATGUURGUUURGUTATRGUUUURGRGUTUTTUTURGUURGUURGURGAGUTGUA82TGUAGUTRGGRGGGRGGGRGGAGAAGAGRGRGGGGGRGATAGRGGGGRGGGUATGGGAGRGGGGUURGURGAGGRGGGGRGGGAUTRGAGAUUAUAGUUURGGAUUTUAUAAGRGGATGURGGGGUTTUTUUTGGUTGUUUUAGRGUUXGRGGATUTGTUTGURGAGGRGRGUTTUUAUTUUUAGAGTTTATTUUTRGTTUUTTUTTUAGTUUTGUTRGTRGGAGGAUURGGTTGUUATGGTGAAGGAAAAAGGTAATTATAAATATRGATUAUTGTGUATGGTTGUAGAAGTTGGAATG83TATGATGUUAGTGGTTGAATAUUTTAGTAGAGAAAAATUTTGAATAATUAAURGGAGGTTUAGGAGAUAGUTGGGTATTTGAGAGUUTATGAGTUAUATAAGUAAUUTTGGAGUUAAGTTGTATTUTUTGTTTGGUUTUAGAGUUAGTUTXGAGUAUATGUAGUUAGAUTGURGGUAGAGAAGATGTGGAGUTGGUATTUTGGUTTAGGUUTGAGUAAGGTRGTGGAAGUUUUAGGTTUUTGAUUATGGUURGUAUAGAGUUATGUTUUAGUUUTGGGTUTUAGUAGGUAGUUAGGTGAG84UTUAUUTGGUTGUUTGUTGAGAUUUAGGGUTGGAGUATGGUTUTGTGRGGGUUATGGTUAGGAAUUTGGGGUTTUUARGAUUTTGUTUAGGUUTAAGUUAGAATGUUAGUTUUAUATUTTUTUTGURGGUAGTUTGGUTGUATGTGUTXGAGAUTGGUTUTGAGGUUAAAUAGAGAATAUAAUTTGGUTUUAAGGTTGUTTATGTGAUTUATAGGUTUTUAAATAUUUAGUTGTUTUUTGAAUUTURGGTTGATTATTUAAGATTTTTUTUTAUTAAGGTATTUAAUUAUTGGUATUATA85GGGGUTRGUAGTGGUUTAGTUTGUTUTGGGUTTTGUTGGATGUUUTTRGAGAATUAURGRGUAAUUTUUTTUAGAGGUUUAAUAUTUUARGTGUTGAUTTUURGGGUUTGTGTUTUUUUTGURGUAGAUTGAAGXGTTUURGGUTGAAGGTGAGGTTUTGUAUUAAXGAGTRGUAGAAGTUURGGGUAGAGUTGGTGGGGUAGUTTUAGAGGUTGGGATTTGAUATUTUTGAGUAGGAGGTGAURGUUURGGUAUUAGUTGUUTGUUAGATUUTGAAGGAGUAAGGUUTGRGAUUATAUU86GGTATGGTRGUAGGUUTTGUTUUTTUAGGATUTGGUAGGUAGUTGGTGURGGGGRGGTUAUUTUUTGUTUAGAGATGTUAAATUUUAGUUTUTGAAGUTGUUUUAUUAGUTUTGUURGGGAUTTUTGRGAUTXGTTGGTGUAGAAUUTUAUUTTUAGURGGGAAXGUTTUAGTUTGRGGUAGGGGAGAUAUAGGUURGGGAAGTUAGUARGTGGAGTGTTGGGUUTUTGAAGGAGGTTGRGRGGTGATTUTRGAAGGGUATUUAGUAAAGUUUAGAGUAGAUTAGGUUAUTGRGAGUUUU87GRGGGGUUAGUAGRGTGUURGGRGGGAAGRGGTAUAGGRGUTURGGGAAGURGRGUAUUAGUTGUTTUAGUAUUATGURGUTUAGGTRGGURGTGUTUTUUTGRGARGGGTTGAAGATGRGGARGAAUTTUTUURGGUAGUTUAUAGUUAXGATUTTUAGGUUTGTRGGGUTGGGAAGAGAGGAGARGUTGTGAGGAGATGRGGURGGTUUAUURGUAUAGUTGRGRGUUURGUURGGAAAUUAGUTUUAGTURGGRGURGGAGGUTTGGGTUAUTRGUUUUTTAUUTUTGUAGGAGTTU88GAAUTUUTGUAGAGGTAAGGGGRGAGTGAUUUAAGUUTURGGRGURGGAUTGGAGUTGGTTTURGGGRGGGGRGRGUAGUTGTGRGGGTGGAURGGURGUATUTUUTUAUAGRGTUTUUTUTUTTUUUAGUURGAUAGGUUTGAAGATXGTGGUTGTGAGUTGURGGGAGAAGTTRGTURGUATUTTUAAUURGTRGUAGGAGAGUARGGURGAUUTGAGRGGUATGGTGUTGAAGUAGUTGGTGRGRGGUTTUURGGAGRGUUTGTAURGUTTUURGURGGGUARGUTGUTGGUUURGU89AGGAGTGTTTGGGGTGUTTUUTUTTGGUTGUAGTGGGAUAUAGGTGTGUUTTUUTAGGAAUTGGGUUUTGAUTAUTTUUAGUUUAAUAUTUURGGGUUTGTGAAUTGTGAUUTGTGTGURGGGATGGGTTTTGTGGGTUTGUUUUATUUUXGUAUTGUTGGATUTGGUUAAGTGGGTGAAGGUTAAGGURGGTUAGAGTTGAGTTTUTGUUTTGTUUUUTUTUUTGGGUTAGATGUUAUAUUAGGUUUAGTGAUTUATAGGGUAGGUAGTTGGGAAATAUUAGGUAGAGGGUAGGTUUTG90UAGGAUUTGUUUTUTGUUTGGTATTTUUUAAUTGUUTGUUUTATGAGTUAUTGGGUUTGGTGTGGUATUTAGUUUAGGAGAGGGGAUAAGGUAGAAAUTUAAUTUTGAURGGUUTTAGUUTTUAUUUAUTTGGUUAGATUUAGUAGTGXGGGGATGGGGUAGAUUUAUAAAAUUUATUURGGUAUAUAGGTUAUAGTTUAUAGGUURGGGAGTGTTGGGUTGGAAGTAGTUAGGGUUUAGTTUUTAGGAAGGUAUAUUTGTGTUUUAUTGUAGUUAAGAGGAAGUAUUUUAAAUAUTUUT91GUAGGAATUAGGUUAGRGTATGTAATGAAAAUTUTTGRGTTATUTTTTTAGAAGGATGTGAUTGTATTTTATGAGTATGUAGUAGGGTUAUUAUAUAUUTTTTGUTUUTGGGUUUUTUUUUTGTGTGTAGUUUAGGUUURGGTTTGTGUTXGAGGGUUAGAXGGUUUTATGGTUUUUAGTTTUUTURGTAGATUAUAUAGGGAGGUAGRGAGGUAGGGTGUAAGGATGTTAGGGGTGGAAGGGGTGAUAURGGGAGUAAAGAUTGUTAUUUUTTGGUUTGGATAAAUUTGTUTGAUATTU92GAATGTUAGAUAGGTTTATUUAGGUUAAGGGGTAGUAGTUTTTGUTUURGGTGTUAUUUUTTUUAUUUUTAAUATUUTTGUAUUUTGUUTRGUTGUUTUUUTGTGTGATUTARGGAGGAAAUTGGGGAUUATAGGGURGTUTGGUUUTXGAGUAUAAAUXGGGGUUTGGGUTAUAUAUAGGGGAGGGGUUUAGGAGUAAAAGGTGTGTGGTGAUUUTGUTGUATAUTUATAAAATAUAGTUAUATUUTTUTAAAAAGATAARGUAAGAGTTTTUATTAUATARGUTGGUUTGATTUUTGU93TGAUTGTATTTTATGAGTATGUAGUAGGGTUAUUAUAUAUUTTTTGUTUUTGGGUUUUTUUUUTGTGTGTAGUUUAGGUUURGGTTTGTGUTRGAGGGUUAGARGGUUUTATGGTUUUUAGTTTUUTURGTAGATUAUAUAGGGAGGUAGXGAGGUAGGGTGUAAGGATGTTAGGGGTGGAAGGGGTGAUAURGGGAGUAAAGAUTGUTAUUUUTTGGUUTGGATAAAUUTGTUTGAUATTUURGAUUTUTGAAGTUATUUATUATGGUTGRGUTGGUTUAGAUAUTTUAAGGGUUAUTTT94AAAGTGGUUUTTGAAGTGTUTGAGUUAGRGUAGUUATGATGGATGAUTTUAGAGGTRGGGAATGTUAGAUAGGTTTATUUAGGUUAAGGGGTAGUAGTUTTTGUTUURGGTGTUAUUUUTTUUAUUUUTAAUATUUTTGUAUUUTGUUTXGUTGUUTUUUTGTGTGATUTARGGAGGAAAUTGGGGAUUATAGGGURGTUTGGUUUTRGAGUAUAAAURGGGGUUTGGGUTAUAUAUAGGGGAGGGGUUUAGGAGUAAAAGGTGTGTGGTGAUUUTGUTGUATAUTUATAAAATAUAGTUA95UAUAUAUUTTTUAGTTGAGGGGRGUTGAGGTUUUTGUTGTTGUTGTGURGTUTGAUUTGTUUUUTUTUTUTGAUAGAGAGUUAGUTGUTUUURGGGAAUAAUTTUAUUAATGAGTGUAAUATAUUAGGUAAUTTUATGTGUAGUAATGGAXGGTGUATUURGGGRGUUTGGUAGTGTGARGGGUTGUUTGAUTGUTTRGAUAAGAGTGATGAGAAGGAGTGURGTGAGTGGUUTGGUUUTTTGUTGGGGTGGGGTGGUAGUUATUUTGGGGUAGAGGGGAGUAGGTUUTGAGUAGGUTTA96TAAGUUTGUTUAGGAUUTGUTUUUUTUTGUUUUAGGATGGUTGUUAUUUUAUUUUAGUAAAGGGUUAGGUUAUTUARGGUAUTUUTTUTUATUAUTUTTGTRGAAGUAGTUAGGUAGUURGTUAUAUTGUUAGGRGUURGGGATGUAUXGTUUATTGUTGUAUATGAAGTTGUUTGGTATGTTGUAUTUATTGGTGAAGTTGTTUURGGGGAGUAGUTGGUTUTUTGTUAGAGAGAGGGGAUAGGTUAGARGGUAUAGUAAUAGUAGGGAUUTUAGRGUUUUTUAAUTGAAAGGTGTGTG97UATGUATTTTGTGTTTGTAGTGTGUTGGUUARGGGAGUAUTUTAAAUAUATTATGGGURGGGRGUAGTGGUTURGGUUTGTAATUTUAGUAUTTTGGGAGGUTGAGGRGGGUAGATUAUTTGAGUUUAGGAGTTXGAUAUUAGUUTGGUUAAUAXGGXGAAAUUUXGTUTUTAUTAAAAATAUAAAAATTAAURGGGTGTGATGGRGRGTGUUTGTATTUUUAGUTAUTAGGGAGGUTGAGGUAGGAGAATUTUUTGAAUUTGGGAGGUAGGGAUTGUAGTGAGUUAAGATTGTGUUAUT98AGTGGUAUAATUTTGGUTUAUTGUAGTUUUTGUUTUUUAGGTTUAGGAGATTUTUUTGUUTUAGUUTUUUTAGTAGUTGGGAATAUAGGUARGRGUUATUAUAUURGGTTAATTTTTGTATTTTTAGTAGAGAXGGGGTTTXGUXGTGTTGGUUAGGUTGGTGTXGAAUTUUTGGGUTUAAGTGATUTGUURGUUTUAGUUTUUUAAAGTGUTGAGATTAUAGGURGGAGUUAUTGRGUURGGUUUATAATGTGTTTAGAGTGUTUURGTGGUUAGUAUAUTAUAAAUAUAAAATGUATG99GGAUTGTGGGUUUUTTGGTTTGTGTUTGAAAGUTGGGGGTAUAGTTUTGUATGGGTTGGUUUUTGUUTTAUUTRGGGAAGUTUUUAGAGUUTGUTGGGUAGUUTGUUTUUTUUTUTUAUUTUUTUXGTUTUUAUTUUUTUUTUAUUAUATTURGGUTUTUUUARGGURGGAGGUXGTGAATGGGUTGUTTTGTTGUURGGUUUAUAUAGGAGGATGGTGGUAGAAGAUUURGGUAUAAAGTUAGUAUUUAUTUTGTTUUUAGGUTGGGTTUAGGGAGGUTGAAAAGUUAUTTUAGUTGTG100UAUAGUTGAAGTGGUTTTTUAGUUTUUUTGAAUUUAGUUTGGGAAUAGAGTGGGTGUTGAUTTTGTGURGGGGTUTTUTGUUAUUATUUTUUTGTGTGGGURGGGUAAUAAAGUAGUUUATTUARGGUUTURGGURGTGGGAGAGURGGAATGTGGTGAGGAGGGAGTGGAGARGGAGGAGGTGAGAGGAGGAGGUAGGUTGUUUAGUAGGUTUTGGGAGUTTUURGAGGTAAGGUAGGGGUUAAUUUATGUAGAAUTGTAUUUUUAGUTTTUAGAUAUAAAUUAAGGGGUUUAUAGTUU101TAUTUTUTTGATGTATGAUUTTGGATGTGATTTAGUUTUTUTGGGUUTTGGUUURGUTGAAUUATGTGATUAGAGUAUUAAGURGGUUTUUUARGUTGGTUTGAGUTGUTUAAGGGUUATUTAGGTUUTUTTTGTUUUAAGUUAGAGGTXGUUTUTUUURGGUUAAGURGRGGUTATGGGGGTGGTGGTAUAAUAGAGAGUAUAGGGAUTTTGGAAUAUAAUAUTGGGTUATGAUUUUTGUUTGGUUAUTUTTGGUTGUTGAUUTTGAUUUTUTGTUTUUTUUTTTGTGAATGGGGGGAGT102AUTUUUUUUATTUAUAAAGGAGGAGAUAGAGGGTUAAGGTUAGUAGUUAAGAGTGGUUAGGUAGGGGTUATGAUUUAGTGTTGTGTTUUAAAGTUUUTGTGUTUTUTGTTGTAUUAUUAUUUUUATAGURGRGGUTTGGURGGGGAGAGGXGAUUTUTGGUTTGGGAUAAAGAGGAUUTAGATGGUUUTTGAGUAGUTUAGAUUAGRGTGGGAGGURGGUTTGGTGUTUTGATUAUATGGTTUAGRGGGGUUAAGGUUUAGAGAGGUTAAATUAUATUUAAGGTUATAUATUAAGAGAGTA103GUUATGGAGAAAATATGUUATGTUTUUATGGAAAUUAAUUTATTTGUTTAAUTGAGGTTUTGGGGGTGGTTUTGAUAUTUAGTGUTAAUUAGGGGGAGTUTGGUTGTGAGGTRGTUAGUAUATGGRGGTGUTGURGGUTGUUTUUUAXGUAXGUAGGUTUTGUUAGUUTGUUTTGUUAATUTGUUAGGUAAUTGGGAUAGGTGUAGAUATGAUUUAGGUTUUAAGUAUARGUATUUAUUUTUUURGURGAGGUAUTUTUURGGTGUUATATGTTGAUTUTGUUUAGRGUUAGGUAGUUUA104TGGGUTGUUTGGRGUTGGGUAGAGTUAAUATATGGUAURGGGAGAGTGUUTRGGRGGGGAGGGTGGATGRGTGTGUTTGGAGUUTGGGTUATGTUTGUAUUTGTUUUAGTTGUUTGGUAGATTGGUAAGGUAGGUTGGUAGAGUUTGXGTGXGTGGGAGGUAGURGGUAGUAURGUUATGTGUTGARGAUUTUAUAGUUAGAUTUUUUUTGGTTAGUAUTGAGTGTUAGAAUUAUUUUUAGAAUUTUAGTTAAGUAAATAGGTTGGTTTUUATGGAGAUATGGUATATTTTUTUUATGGU105GAGTUTGGUTGTGAGGTRGTUAGUAUATGGRGGTGUTGURGGUTGUUTUUUARGUARGUAGGUTUTGUUAGUUTGUUTTGUUAATUTGUUAGGUAAUTGGGAUAGGTGUAGAUATGAUUUAGGUTUUAAGUAUARGUATUUAUUUTUUUXGURGAGGUAUTUTUURGGTGUUATATGTTGAUTUTGUUUAGRGUUAGGUAGUUUAGRGUUUAUUTUUUUUTUUUUAGUUTGGUUUUARGUAUAGTGUTUTAGUUTUTGUTGGGTAGTGTGAGGAGTGGUAATUTGUAGGUAUUUTAGAAG106UTTUTAGGGTGUUTGUAGATTGUUAUTUUTUAUAUTAUUUAGUAGAGGUTAGAGUAUTGTGRGTGGGGUUAGGUTGGGGAGGGGGAGGTGGGRGUTGGGUTGUUTGGRGUTGGGUAGAGTUAAUATATGGUAURGGGAGAGTGUUTRGGXGGGGAGGGTGGATGRGTGTGUTTGGAGUUTGGGTUATGTUTGUAUUTGTUUUAGTTGUUTGGUAGATTGGUAAGGUAGGUTGGUAGAGUUTGRGTGRGTGGGAGGUAGURGGUAGUAURGUUATGTGUTGARGAUUTUAUAGUUAGAUTU107GURGAATUURGAGGGURGAGUAUUUUTUUUTUAGURGUAUTGUAUUTGUURGTAGGTGAUUAAUUUARGGGRGGAUUUUUAGAUUUAATUUTUTUUAGAGUUAGGGTGGGATGGGUAGGGAUAGGAGURGGAGGUUUTAUTGGUUURGGGXGAAGGUATUUTGGAAAGUATUUAGAGRGTUUAGUATUUUTUURGRGGUUAUURGUAGGUTGAURGAUUUUTGGGUAGAUUUTUAGAUTUAATUUAGTUUAGGGRGGATTAAGGAGTGGGAGAUAAGGGAGURGGTGGUUURGUTGGUUU108GGGUUAGRGGGGUUAURGGUTUUUTTGTUTUUUAUTUUTTAATURGUUUTGGAUTGGATTGAGTUTGAGGGTUTGUUUAGGGGTRGGTUAGUUTGRGGGTGGURGRGGGAGGGATGUTGGARGUTUTGGATGUTTTUUAGGATGUUTTXGUURGGGGUUAGTAGGGUUTURGGUTUUTGTUUUTGUUUATUUUAUUUTGGUTUTGGAGAGGATTGGGTUTGGGGGTURGUURGTGGGTTGGTUAUUTARGGGUAGGTGUAGTGRGGUTGAGGGAGGGGTGUTRGGUUUTRGGGATTRGGU109TTGUTTGAUUAAAAGAATGUAGUAGAUATAAUTTTGAGAUUTGGAGUTAGGTUAUAAGARGATTTUUTGGGTTTTGTGGAATTUTRGTTUTGAAAGAAAUAAGUUAUUAAGTGGURGGGTGAGUTGGUTUAXGUUTGTAATUUUAGUAUTTTGGGAGGUXGAGURGGGUXGATUAUAAGGTUAGGAGATRGAGAUUATUUTGGUTAAUATGGTGAAAUUURGTUTUTAUTAAAAATAUAAAAAAATTAGURGGGUATAUTGGRGGGRGUUTGTAGTUUUAGUTAUTRGGGAGGUTGAGGU110GUUTUAGUUTUURGAGTAGUTGGGAUTAUAGGRGUURGUUAGTATGUURGGUTAATTTTTTTGTATTTTTAGTAGAGARGGGGTTTUAUUATGTTAGUUAGGATGGTUTRGATUTUUTGAUUTTGTGATXGGUURGGUTXGGUUTUUUAAAGTGUTGGGATTAUAGGXGTGAGUUAGUTUAUURGGUUAUTTGGTGGUTTGTTTUTTTUAGAARGAGAATTUUAUAAAAUUUAGGAAATRGTUTTGTGAUUTAGUTUUAGGTUTUAAAGTTATGTUTGUTGUATTUTTTTGGTUAAGUAA111AGAATUTGUUTAGUAGGRGGUTUTUUUUTGUTUUUUUAURGAGUAUAGAURGTGGGAGGGGAUUUTGRGGGAGGAGGUTGUTTUAGTUTUUAGAGAUUATUTUUUATUTUTAUAGRGAUTUUUUTATGAURGTUUUUUAUURGGTGUTUTXGGGUUARGGGGAAGGGAUAUTRGGGAAAGAUAUUAGAGAURGGGAGGGTGUAGUTGGGUTUTTRGRGGGGAGRGGGRGGGAGGUUTTUUTGTTAUATGTRGUAGUTGGGAUAUAGARGGUAGRGUTUUAGGGTUUAUTTGURGGUTTRG112RGAAGURGGUAAGTGGAUUUTGGAGRGUTGURGTUTGTGTUUUAGUTGRGAUATGTAAUAGGAAGGUUTUURGUURGUTUUURGRGAAGAGUUUAGUTGUAUUUTUURGGTUTUTGGTGTUTTTUURGAGTGTUUUTTUUURGTGGUUXGAGAGUAURGGGTGGGGGARGGTUATAGGGGAGTRGUTGTAGAGATGGGAGATGGTUTUTGGAGAUTGAAGUAGUUTUUTUURGUAGGGTUUUUTUUUARGGTUTGTGUTRGGTGGGGGAGUAGGGGAGAGURGUUTGUTAGGUAGATTUT113AGGUUUAGGUAGAGGTUAGAGUUUAAGUUUTGTUUURGAAGGAAATGTGTUUUATGUTAAUTAUTUUATAGUTGAGGUUTGGAGGGAAGTUAGGGAUUUTGGGAUTGGTTATUUTGGUUTTGAUTUATTAUTGTTURGGAGAUUTAAAXGUAUUUTGAGUUAUUAGAXGTGGGTGTTAAUAUUTGAGGTUAAUUUUUTGAXGUTTURGGUTGUTUTGGAGGAAGUTGGTUUTUUUTUUUAUUTUUTGTTTTURGTGUUAGUUTGGTAUAGAGTUAAGGGGUTTGGUTGGGUTTGGUTGGG114UUAGUUAAGUUUAGUUAAGUUUUTTGAUTUTGTAUUAGGUTGGUARGGAAAAUAGGAGGTGGGAGGGAGGAUUAGUTTUUTUUAGAGUAGURGGAAGXGTUAGGGGGTTGAUUTUAGGTGTTAAUAUUUAXGTUTGGTGGUTUAGGGTGXGTTTAGGTUTURGGAAUAGTAATGAGTUAAGGUUAGGATAAUUAGTUUUAGGGTUUUTGAUTTUUUTUUAGGUUTUAGUTATGGAGTAGTTAGUATGGGAUAUATTTUUTTRGGGGAUAGGGUTTGGGUTUTGAUUTUTGUUTGGGUUTG115UUUATGUTAAUTAUTUUATAGUTGAGGUUTGGAGGGAAGTUAGGGAUUUTGGGAUTGGTTATUUTGGUUTTGAUTUATTAUTGTTURGGAGAUUTAAAXGUAUUUTGAGUUAUUAGAXGTGGGTGTTAAUAUUTGAGGTUAAUUUUUTGAXGUTTURGGUTGUTUTGGAGGAAGUTGGTUUTUUUTUUUAUUTUUTGTTTTURGTGUUAGUUTGGTAUAGAGTUAAGGGGUTTGGUTGGGUTTGGUTGGGUTUAGAAARGTGGUAGTUAGGAGUUAGUUTGRGGGUAGRGGGGTGUTGGG116UUUAGUAUUURGUTGUURGUAGGUTGGUTUUTGAUTGUUARGTTTUTGAGUUUAGUUAAGUUUAGUUAAGUUUUTTGAUTUTGTAUUAGGUTGGUARGGAAAAUAGGAGGTGGGAGGGAGGAUUAGUTTUUTUUAGAGUAGURGGAAGXGTUAGGGGGTTGAUUTUAGGTGTTAAUAUUUAXGTUTGGTGGUTUAGGGTGXGTTTAGGTUTURGGAAUAGTAATGAGTUAAGGUUAGGATAAUUAGTUUUAGGGTUUUTGAUTTUUUTUUAGGUUTUAGUTATGGAGTAGTTAGUATGGG117UTUTUUURGUAGTTTUATURGTUUTUUTUUURGUUTUTGRGAGUTGGGTTTGGGGARGTUTGGGTGGAATGTAGAUUUAUAGGUTGTUUTTGGTGUUUTTUUTUUUTGTTUTUUAGRGUUUUAGUUUUAGAUAUUAGTUUUUUAGRGGGXGAAAGUURGGGAGRGUUTTUUURGAAAGAUATUAGGGTGUUARGRGGUUUUTGUUUTGUAGAAGUATUUUUUTUURGUUUUTGUUTGGAAAGUAGGUUUUTUUUTAAGUTUTGRGUUUTTUTTUUUTGGGRGUUUTRGGAURGTGGUURG118RGGGUUARGGTURGAGGGRGUUUAGGGAAGAAGGGRGUAGAGUTTAGGGAGGGGUUTGUTTTUUAGGUAGGGGRGGGAGGGGGATGUTTUTGUAGGGUAGGGGURGRGTGGUAUUUTGATGTUTTTRGGGGAAGGRGUTUURGGGUTTTXGUURGUTGGGGGAUTGGTGTUTGGGGUTGGGGRGUTGGAGAAUAGGGAGGAAGGGUAUUAAGGAUAGUUTGTGGGTUTAUATTUUAUUUAGARGTUUUUAAAUUUAGUTRGUAGAGGRGGGGAGGAGGARGGATGAAAUTGRGGGGAGAG119AGAGGAGTGGGGAGRGUAGUAGGGTGGUUUURGUTUURGUTUAGAGGAGUTGGUUUTTTAAGGUUAGGUUUAGGRGGGTRGGGAAUAGAGAUURGGGAATGTGGGUTGGAUTGGGGAGUAGAGUUAUUUAGUATGAGTUATTUURGTTTXGURGGAUTUTTRGURGUTGGUTUTRGUTTGURGUUUTUUUUTGGUUUTGGUUUTGGUUTUTGRGUUUTUUUTGUAGAGUTGGTURGGGTGGGUTGGRGGUUTUUAUURGUUAUAAGRGUAUAGGGUTUTGUUUAUTUUURGUUUUTTTTU120GAAAAGGGGRGGGGAGTGGGUAGAGUUUTGTGRGUTTGTGGRGGGTGGAGGURGUUAGUUUAUURGGAUUAGUTUTGUAGGGAGGGRGUAGAGGUUAGGGUUAGGGUUAGGGGAGGGRGGUAAGRGAGAGUUAGRGGRGAAGAGTURGGXGAAARGGGAATGAUTUATGUTGGGTGGUTUTGUTUUUUAGTUUAGUUUAUATTUURGGGTUTUTGTTUURGAUURGUUTGGGUUTGGUUTTAAAGGGUUAGUTUUTUTGAGRGGGAGRGGGGGUUAUUUTGUTGRGUTUUUUAUTUUTUT121GURGAGRGRGGTGGUTUATGUUTGTAATUUUAGUAUTTTGGGAGARGGAGGTGGGTGGATUAUUTUAGGTUAGAAGTTTGAGAUUTUTGTUTUTAUTGAAAUTATAAAAAATTGGURGGGUATGGTGGTGGGTGTUTGTAGTTUUAGUTAXGTGGTAAGUTGAGGUAGGAGAATGAUTTGAAUURGGGAGGRGGAGGTTGUAGTGAGUUAGGATTGRGUUAUTGUAUTUUAGUUTGGGAGAUAGAGTUAGAUTUTGTUTUAAAAAAAAGUTATGGGUUTGUAGGATGUUTAATATAAAAG122UTTTTATATTAGGUATUUTGUAGGUUUATAGUTTTTTTTTGAGAUAGAGTUTGAUTUTGTUTUUUAGGUTGGAGTGUAGTGGRGUAATUUTGGUTUAUTGUAAUUTURGUUTUURGGGTTUAAGTUATTUTUUTGUUTUAGUTTAUUAXGTAGUTGGAAUTAUAGAUAUUUAUUAUUATGUURGGUUAATTTTTTATAGTTTUAGTAGAGAUAGAGGTUTUAAAUTTUTGAUUTGAGGTGATUUAUUUAUUTURGTUTUUUAAAGTGUTGGGATTAUAGGUATGAGUUAURGRGUTRGGU123UARGUTUUTGTTTUAUTTTUATGTTUTGUTUTGTAUAUUTGGUTURGUUTTUTAGATAGUAATAGUAGAATTAGTGAAAGTATTAAAGTUTTTGATUTTTUTGAGAAGAGUATAGAAGAAATAATGARGTAAGUTGTUUTUTUTUUAGUTXGGUTAUUTAAAAGGGAAAGGUUUUUTGTURGGTGGAUARGTGAUTUAUATGAUUTTATTAATUAUTGGAGATGAUTUAUAUTUUTTAUUUTGUUUUTTTGUUTTGTAUAUAATAAATAAUAGRGRGAUUAGGUATTRGGGGUUAUTGUU124GGUAGTGGUUURGAATGUUTGGTRGRGUTGTTATTTATTGTGTAUAAGGUAAAGGGGUAGGGTAAGGAGTGTGAGTUATUTUUAGTGATTAATAAGGTUATGTGAGTUARGTGTUUAURGGAUAGGGGGUUTTTUUUTTTTAGGTAGUXGAGUTGGAGAGAGGAUAGUTTARGTUATTATTTUTTUTATGUTUTTUTUAGAAAGATUAAAGAUTTTAATAUTTTUAUTAATTUTGUTATTGUTATUTAGAAGGRGGAGUUAGGTGTAUAGAGUAGAAUATGAAAGTGAAAUAGGAGRGTG125AGUUUUUTGGGRGGGGTURGGGGAGUAGGUURGUATTTGGAGGAUAGGGTGTGAUUUATUTGAATUUTRGTTAAAGTAAAAGURGAURGARGGUTUTGGGAGGTTTGAGGUUTGGRGGGGRGGUUURGGGAAGTGATTTGTGGUXGUTAGGXGRGXGUTGGAAAUUUTTTUUUATUTGRGGAGUUUAURGGAGUTGTGATRGGAGGAGGAATTUUUUUAGGUAGGGAGGAURGUAGGGUUTTTTTUAUTRGTUUTGAGGGGUUUTGGGGUTTGGGGAGUAAAUUTGGGGTGAUUUATTTU126GAAATGGGTUAUUUUAGGTTTGUTUUUUAAGUUUUAGGGUUUUTUAGGARGAGTGAAAAAGGUUUTGRGGTUUTUUUTGUUTGGGGGAATTUUTUUTURGATUAUAGUTURGGTGGGUTURGUAGATGGGAAAGGGTTTUUAGXGRGXGUUTAGXGGUUAUAAATUAUTTUURGGGGURGUUURGUUAGGUUTUAAAUUTUUUAGAGURGTRGGTRGGUTTTTAUTTTAARGAGGATTUAGATGGGTUAUAUUUTGTUUTUUAAATGRGGGUUTGUTUUURGGAUUURGUUUAGGGGGUT127UATUUAUAAAUUTUUUAGGUUUUUTUAUTUTTUURGUAUAGTUTGUUTURGGTGUTUUAGAAAGAUTGGAAATGAGGTGAGUTUUUTTGGATUUUTGUUTGUUAUUTGUAAATATUATGTGGTGUTAUTTGUUUTUUTGTUUUTUUTUUXGTUUUAGGUUAATUUTUUUAUUUUUTTAATTGUURGGGGATUTUUATTAUTTAAAUUTTTUUAUTGGTAUUTUTUUTUUUAUAUAAGUUTUUTUAGUTGTTTTURGTUTTTAAUUAAUAUUTTUUUTGGUTUUAGUTAUTGUUAUTTUAT128ATGAAGTGGUAGTAGUTGGAGUUAGGGAAGGTGTTGGTTAAAGARGGAAAAUAGUTGAGGAGGUTTGTGTGGGAGGAGAGGTAUUAGTGGAAAGGTTTAAGTAATGGAGATUUURGGGUAATTAAGGGGGTGGGAGGATTGGUUTGGGAXGGGAGGAGGGAUAGGAGGGUAAGTAGUAUUAUATGATATTTGUAGGTGGUAGGUAGGGATUUAAGGGAGUTUAUUTUATTTUUAGTUTTTUTGGAGUAURGGAGGUAGAUTGTGRGGGAAGAGTGAGGGGGUUTGGGAGGTTTGTGGATG129UTTTUUUAGGAUTGUUTTGGUUUUUTGGUUUUAGTUTGGAGGAUTUTTGUTUAUTTUUTURGUUUUUAGGTGAGUTGAGAAUUUAUTGRGRGRGGGAUTUTGUTGRGUUTGUUUTUURGGGUTGUAGAGGGUAGGAXGUAURGUUAGGUAAGGURGRGGUTUTGXGUTGATGUUAUTURGGGAGRGGGTGGUTGRGGGGGAGGAGGGRGAGUAUTGGARGGGGGUAGRGGAGTGTAGGGTGTGAGATUTAAAUAGAGGGUTUUAUTGGAGGGUTTGUUUAGAAGGRGGUAGTUAUAUTGG130UUAGTGTGAUTGURGUUTTUTGGGUAAGUUUTUUAGTGGAGUUUTUTGTTTAGATUTUAUAUUUTAUAUTURGUTGUUUURGTUUAGTGUTRGUUUTUUTUUUURGUAGUUAUURGUTUURGGAGTGGUATUAGXGUAGAGURGRGGUUTTGUUTGGRGGTGXGTUUTGUUUTUTGUAGUURGGGAGGGUAGGRGUAGUAGAGTUURGRGRGUAGTGGGTTUTUAGUTUAUUTGGGGGRGGAGGAAGTGAGUAAGAGTUUTUUAGAUTGGGGUUAGGGGGUUAAGGUAGTUUTGGGAAAG131TTTAGGGTUTUTUTUURGUUTUTTTTUUTUUUURGUTUUUTUTUTUUTTGRGGUTGAUTUUAGUTUUUUUTRGGTGUURGTAAUUUTUUTTTUUTUTTTTTGUXGUAGTUTUXGTUTUTUTTUUAUAGGGTUTUTUUUTUUUUUTUTUUURGTGGTTGTUAGAUTTTUTUUTGGAUTTTUTURGUUURGUAURGUUXGUUURGGATGURGAGRGTGGTAGAUTUTGUAGURGGGUTUUTRGUTGUURGUTGGRGUTGUUTAUAUUUUUTTGGGUTUUUUTUUAAGGTUUUUTURGUTRGU132GRGAGRGGAGGGGAUUTTGGAGGGGAGUUUAAGGGGGTGTAGGUAGRGUUAGRGGGUAGRGAGGAGUURGGUTGUAGAGTUTAUUARGUTRGGUATURGGGGXGGGRGGTGRGGGGRGGAGAAAGTUUAGGAGAAAGTUTGAUAAUUARGGGGAGAGGGGGAGGGAGAGAUUUTGTGGAAGAGAGAXGGAGAUTGXGGUAAAAAGAGGAAAGGAGGGTTARGGGUAURGAGGGGGAGUTGGAGTUAGURGUAAGGAGAGAGGGAGRGGGGGAGGAAAAGAGGRGGGAGAGAGAUUUTAAA133GAGGGUUAUAGTAAAUTGGAUAAGTTTTTUTGUUUAGUUTAGGUTGUUAUUTGTAGGTUAUTTGGGUTUUAGUTATGTGGUTGUUTUTTUTGUTGGGTGUUTTAUTUTGGGUAGTGUTGTGGTTGUTUAGGGAURGGUAGAGUUTGUUXGUUAGUAATGUUTTTGTUTTUATUAURGGUTGTGAUTUAGGUTTTGGGRGUUTTUTGGUAUTGUAGUTGGAUUAGAGAGGUTTURGAGTUUTGGUUAGUTGUUTGAUUUUUTURGGGGURGAGGAUUTGUAGRGGGTGGUUTUUTUURGUU134GRGGGAGGAGGUUAUURGUTGUAGGTUUTRGGUUURGGAGGGGGTUAGGUAGUTGGUUAGGAUTRGGAAGUUTUTUTGGTUUAGUTGUAGTGUUAGAAGGRGUUUAAAGUUTGAGTUAUAGURGGTGATGAAGAUAAAGGUATTGUTGGXGGGUAGGUTUTGURGGTUUUTGAGUAAUUAUAGUAUTGUUUAGAGTAAGGUAUUUAGUAGAAGAGGUAGUUAUATAGUTGGAGUUUAAGTGAUUTAUAGGTGGUAGUUTAGGUTGGGUAGAAAAAUTTGTUUAGTTTAUTGTGGUUUTUA135GTTUTGGUTTUATTTTTTTTTTUUUAAAATGUUATTTTUATTTGTTUTTAGAGTTUAGAAUATGTUAAAGAGUTTUTTTAAGUAGTAGGTGGTTTTAUAGAGUUUAUAGAGAAGGAAAAUTAAATATUATUURGGATGUAGTUUAUTAXGATXGTGGAGGAGTUAGATTAUTUTURGGGUTTTGUTGTGTUTGUTTGTGAAAUAGGAAAGGGAGAAUTGAGGUAATGAGTUAUUTUAUTTGGGUUUAAAGUAUUAUUTARGTTGAATATGGAGAAAATGTGAAGUAAGAGTTTUTTTTTA136TAAAAAGAAAUTUTTGUTTUAUATTTTUTUUATATTUAARGTAGGTGGTGUTTTGGGUUUAAGTGAGGTGAUTUATTGUUTUAGTTUTUUUTTTUUTGTTTUAUAAGUAGAUAUAGUAAAGUURGGAGAGTAATUTGAUTUUTUUAXGATXGTAGTGGAUTGUATURGGGATGATATTTAGTTTTUUTTUTUTGTGGGUTUTGTAAAAUUAUUTAUTGUTTAAAGAAGUTUTTTGAUATGTTUTGAAUTUTAAGAAUAAATGAAAATGGUATTTTGGGAAAAAAAAAATGAAGUUAGAAU137UUTUUTUUAGTUTTTGUATATATAUUAGGUTGGTATUUATTGUAGGTGGGGAUUTUUTUTTTGGGUTTTGGAGUUUUUUTUUUTGTGTUTUTGTAURGGGGAGUTTUTTUUTTUTGTUTTUTUUUTTUUTTUTTGUTUATTAAAUTUTUXGUTUUTTAAAAUUAUTUUARGTGTGTURGTGTTGTTTTATUTAAAURGGRGGUAGGATUAAGAAUUUTTGTGTTUUTGUAUTUATUAGAGURGTATGATAATUAAGAGUTGAUTAUUTGGGUUATTUTUATAUUATTAGTGURGUATTTA138TAAATGRGGUAUTAATGGTATGAGAATGGUUUAGGTAGTUAGUTUTTGATTATUATARGGUTUTGATGAGTGUAGGAAUAUAAGGGTTUTTGATUUTGURGURGGTTTAGATAAAAUAAUARGGAUAUARGTGGAGTGGTTTTAAGGAGXGGAGAGTTTAATGAGUAAGAAGGAAGGGAGAAGAUAGAAGGAAGAAGUTUUURGGTAUAGAGAUAUAGGGAGGGGGGUTUUAAAGUUUAAAGAGGAGGTUUUUAUUTGUAATGGATAUUAGUUTGGTATATATGUAAAGAUTGGAGGAGG139AAGGTTAAAGTRGUTGUTAGAUUAAGGUTAAAURGTGGRGAGGTAGTTGUTTGRGURGUAGAGTGTGGGTGTGAAUAGUTGGAGUTUAGTGGTTUUTGGAGAUTUAGGGAUUAUUTGTATTUUAUATURGGUTTUUUAUUUARGUAUAXGUAGTATGAUUTGGGTTTUUUUTTTATAUAGTGGAATGUTAAGTGUUTAUAUUUTAGURGGGGTUAGUUAAUTATGGUUTGTGGGUAUUATUUUAUUTGUAGUUTGTTTTTGAGUTAAGAATGTTGTTGAUAUTTTTAAAAAUAGAGAAUA140GTTUTUTGTTTTTAAAAGTGTUAAUAAUATTUTTAGUTUAAAAAUAGGUTGUAGGTGGGATGGTGUUUAUAGGUUATAGTTGGUTGAUUURGGUTAGGGTGTAGGUAUTTAGUATTUUAUTGTATAAAGGGGAAAUUUAGGTUATAUTGXGTGTGRGTGGGTGGGAAGURGGATGTGGAATAUAGGTGGTUUUTGAGTUTUUAGGAAUUAUTGAGUTUUAGUTGTTUAUAUUUAUAUTUTGRGGRGUAAGUAAUTAUUTRGUUARGGTTTAGUUTTGGTUTAGUAGRGAUTTTAAUUTTG141GAGAUAGGGTTTUAUTUUTGTRGUUUAGGUTGGAGTGUAGUUTUAAUUTUUTGGGUTUAGTGGATUTTUUUAUUTUAGAUTUUTGAGTAGURGGGAUTAUAGGUAUARGUUAUUAGGUUTAGUTAATTTTTTGTATTTTTTTGTAGAGAXGAGGTTTRGUTAGGTTGUUUAGGUTGGTUTUTAAUTUUTGGGUTUAAGXGATUUAUUUAUUTUAGUTTUUUAAAGTGUTGGGGTTAUAGGUUTGAGTUAUAGXGTURGGUTGAAAGTGAAGTTGAATGAGATGAUTRGTUUAGGUUAUAT142ATGTGGUUTGGARGAGTUATUTUATTUAAUTTUAUTTTUAGURGGAXGUTGTGAUTUAGGUUTGTAAUUUUAGUAUTTTGGGAAGUTGAGGTGGGTGGATXGUTTGAGUUUAGGAGTTAGAGAUUAGUUTGGGUAAUUTAGRGAAAUUTXGTUTUTAUAAAAAAATAUAAAAAATTAGUTAGGUUTGGTGGRGTGTGUUTGTAGTUURGGUTAUTUAGGAGTUTGAGGTGGGAAGATUUAUTGAGUUUAGGAGGTTGAGGUTGUAUTUUAGUUTGGGRGAUAGGAGTGAAAUUUTGTUTU143AUARGUUAUUAGGUUTAGUTAATTTTTTGTATTTTTTTGTAGAGAXGAGGTTTRGUTAGGTTGUUUAGGUTGGTUTUTAAUTUUTGGGUTUAAGXGATUUAUUUAUUTUAGUTTUUUAAAGTGUTGGGGTTAUAGGUUTGAGTUAUAGXGTURGGUTGAAAGTGAAGTTGAATGAGATGAUTRGTUUAGGUUAUATGGUAATUAGTGGUTGATTGARGUUAAAGTTGATTTUATTUTTUTUAATGGGTTUAGAGTUUAAATTUTGGAAUUTUAGAAGARGTTGUTATTUTGGTTUUAAGU144UTTGGAAUUAGAATAGUAARGTUTTUTGAGGTTUUAGAATTTGGAUTUTGAAUUUATTGAGAAGAATGAAATUAAUTTTGGRGTUAATUAGUUAUTGATTGUUATGTGGUUTGGARGAGTUATUTUATTUAAUTTUAUTTTUAGURGGAXGUTGTGAUTUAGGUUTGTAAUUUUAGUAUTTTGGGAAGUTGAGGTGGGTGGATXGUTTGAGUUUAGGAGTTAGAGAUUAGUUTGGGUAAUUTAGRGAAAUUTXGTUTUTAUAAAAAAATAUAAAAAATTAGUTAGGUUTGGTGGRGTGTG145AGTGAUTGUAGRGTUAGGUUAAGUTTGGUUAUTTAUATGTUTGGUATGAUAGTGGUUTUAGAGTAUTRGTUTGAGAAGAAGAGUTATUAUUTGAGRGUTUTGGAGAAUTTAGURGGAGUTTTUAGGUAGTUTGGGAGUUTAUATGGAGGXGTGTAGGUTTATGTUTUATGTUUARGTTGUURGGGAGAUAAAATUUTTTTUTATTTAGAGUTGUUUUAAAATGTTUTGUAUUAGUTTUTUAUTGRGGTGGUTTUAUUTTAGUATAUAGGTATGTGGARGGUUAUTGTGUTGGUTUAUUTT146AAGGTGAGUUAGUAUAGTGGURGTUUAUATAUUTGTATGUTAAGGTGAAGUUAURGUAGTGAGAAGUTGGTGUAGAAUATTTTGGGGUAGUTUTAAATAGAAAAGGATTTTGTUTUURGGGUAARGTGGAUATGAGAUATAAGUUTAUAXGUUTUUATGTAGGUTUUUAGAUTGUUTGAAAGUTURGGUTAAGTTUTUUAGAGRGUTUAGGTGATAGUTUTTUTTUTUAGARGAGTAUTUTGAGGUUAUTGTUATGUUAGAUATGTAAGTGGUUAAGUTTGGUUTGARGUTGUAGTUAUT147RGGGUAUUTAGGTUTRGUURGUUTGUAGURGUUTGGGGARGRGGGTTURGGARGGUTGGRGRGGGGRGGGGRGGGGAUUAURGAGUAGGAAGTUUURGRGGAAGRGURGURGGGUAUAGRGTGGGTGUTGTRGAGGAGTGGRGUURGGGXGGGGRGGGAGGTTATAAATAGRGGURGUUATUUTGUTTUTUTTUAGAUAUAUTTAATTTAGURGGUAGGUAUARGGATGUTTATTTTTAAAAAAAGAAUTTGTTTTATTGRGUTRGAGGTGAURGGGAAGGTGTUUURGRGGGTUAUTRG148RGAGTGAUURGRGGGGAUAUUTTUURGGTUAUUTRGAGRGUAATAAAAUAAGTTUTTTTTTTAAAAATAAGUATURGTGTGUUTGURGGUTAAATTAAGTGTGTUTGAAGAGAAGUAGGATGGRGGURGUTATTTATAAUUTUURGUUUXGUURGGGRGUUAUTUUTRGAUAGUAUUUARGUTGTGUURGGRGGRGUTTURGRGGGGAUTTUUTGUTRGGTGGTUUURGUUURGUUURGRGUUAGURGTURGGAAUURGRGTUUUUAGGRGGUTGUAGGRGGGRGAGAUUTAGGTGUURG149GAAGGTGRGGTGRGGTGAGGTGAGAAGAGAGAURGRGUTAGAUUAGGRGATGTUTTAGGGARGGGAGAGGGGTGAGGUUUARGGRGGTUUTGGGGAGRGGUUUARGAURGGUUUARGUAGAGUTTGTAGUUAGTGAAUAGGAAGTATTGGXGAGAGGGAUTGAGAAAUUUAAGAGAGTGTGGGGTGAGGAAAAGGTUAAGGAAGGUUUAGGUTTUUAGGAAGGGUUTGGGURGGGGRGGGGRGGGTGGTGGGAGGUAGTGGTTAGGARGGGRGGGGGTGGGGGTGGGGGTGGGGGTAGGG150UUUTAUUUUUAUUUUUAUUUUUAUUUURGUURGTUUTAAUUAUTGUUTUUUAUUAUURGUUURGUUURGGUUUAGGUUUTTUUTGGAAGUUTGGGUUTTUUTTGAUUTTTTUUTUAUUUUAUAUTUTUTTGGGTTTUTUAGTUUUTUTXGUUAATAUTTUUTGTTUAUTGGUTAUAAGUTUTGRGTGGGURGGTRGTGGGURGUTUUUUAGGAURGURGTGGGUUTUAUUUUTUTUURGTUUUTAAGAUATRGUUTGGTUTAGRGRGGTUTUTUTTUTUAUUTUAURGUAURGUAUUTTU151GAGAAAUAAAATAUATTTTTTAATTTAAAAAAAAGTAUUAGAATGAATAAAAUAGGGGUTTTUUAAAAUTGUTTTTGGTAGATTTAGUAAAUUTAUTGAAUTTAGAAAUTTTUATTTTATAATTGTURGGAGATAGAAAGUAGTGUTTUXGAATAAGTGGATAAUTUTGURGGTUUUAGTAGGTGUUATTGGTGAGUAUAUAGGGTTGUTTAAGTUTUTAAGTUATTTUUUTGAUTGTGGTTTGAATUAATGTUAAATATUTAUAGGGGTUAGGUAGGTAAUTUAATGAAGTGAAAUAGG152UTGTTTUAUTTUATTGAGTTAUUTGUUTGAUUUUTGTAGATATTTGAUATTGATTUAAAUUAUAGTUAGGGAAATGAUTTAGAGAUTTAAGUAAUUUTGTGTGUTUAUUAATGGUAUUTAUTGGGAURGGUAGAGTTATUUAUTTATTXGGAAGUAUTGUTTTUTATUTURGGAUAATTATAAAATGAAAGTTTUTAAGTTUAGTAGGTTTGUTAAATUTAUUAAAAGUAGTTTTGGAAAGUUUUTGTTTTATTUATTUTGGTAUTTTTTTTTAAATTAAAAAATGTATTTTGTTTUTUT153GGAGGGUTTUAURGTUAGRGTAGRGTARGUUTGRGGGURGGGGRGGGAGAGGGAURGTRGRGTTTGTGURGUUAGUAUUTGRGGUUUUUAGRGUAUURGGGUUUUARGRGGTAGUUUUUAGGGAGTGGGGAGTRGGGRGGGAAAUAGUTXGUURGGGUTUUTARGGGTGUUUUTTTRGURGRGUTUUUTUURGAGGGTUUTTTGUAGTRGGGRGTGGAAGTGGGATGAGUAAAUUURGUAGUAUAGGGUUTTRGUUUUAGGAUUTGUAUUUTUTAURGGUUARGGGARGTUUUTURGUAU154GTGRGGAGGGARGTUURGTGGURGGTAGAGGGTGUAGGTUUTGGGGRGAAGGUUUTGTGUTGRGGGGTTTGUTUATUUUAUTTUUARGUURGAUTGUAAAGGAUUUTRGGGAGGGAGRGRGGRGAAAGGGGUAUURGTAGGAGUURGGGXGAGUTGTTTUURGUURGAUTUUUUAUTUUUTGGGGGUTAURGRGTGGGGUURGGGTGRGUTGGGGGURGUAGGTGUTGGRGGUAUAAARGRGARGGTUUUTUTUURGUUURGGUURGUAGGRGTARGUTARGUTGARGGTGAAGUUUTUU155AGAUAUAAAGAGGGRGGAGAGAUAGAUAUAGAAAGAGGGAGAUAGRGGGGUTGGATGGARGTGTGGURGGGUUAGTGGGGAGGAGAGARGAGTURGUAGAUAGRGTTUAGAGGURGRGUTGUUTGGGTGUTGAGURGTUURGGGGTTUAXGGTRGUAGTTTGTUUTTAUAAAARGUUUAGURGUUURGAUUTGTGGTGUTTAGGGAGGAUUTAUUTGGUTGTGURGGTUTGAGAAGGGGUUAGTGAGGUURGGTGRGGGTARGGGRGGGTGUAGATGUAGUUAGGAGGARGGGRGGGAGU156GUTUURGUURGTUUTUUTGGUTGUATUTGUAUURGUURGTAUURGUAURGGGUUTUAUTGGUUUUTTUTUAGAURGGUAUAGUUAGGTAGGTUUTUUUTAAGUAUUAUAGGTRGGGGRGGUTGGGRGTTTTGTAAGGAUAAAUTGRGAUXGTGAAUUURGGGARGGUTUAGUAUUUAGGUAGRGRGGUUTUTGAARGUTGTUTGRGGAUTRGTUTUTUUTUUUUAUTGGUURGGUUAUARGTUUATUUAGUUURGUTGTUTUUUTUTTTUTGTGTUTGTUTUTURGUUUTUTTTGTGTUT157GUTGTUAUAUTGAGUTGTTTAAUAUTTAAGATGTTGGTGGATGGUAAAGUTAAAAGAGUAUTGTAAUAUATGAUUTUTGGGGUTUURGGAGTUATGAGTAUUUUTTUTAGAUAUAGURGTGGGGUUAUAUAGAATTUTGUTUUTGUTGUXGUURGGAAGUAUTUATUTGGUTUUTGUAUUUAUTUAUUTGUATUUTUUUUUTUUUARGAGGTGTTAAGAGUTGTGGGATGAGTAAAGGAGGUUTGTGAAGGATTTUUTGTTTUAGTUTTAUATTUAGGTUTGAGTTUTUAGAGGAATUTT158AAGATTUUTUTGAGAAUTUAGAUUTGAATGTAAGAUTGAAAUAGGAAATUUTTUAUAGGUUTUUTTTAUTUATUUUAUAGUTUTTAAUAUUTRGTGGGAGGGGGAGGATGUAGGTGAGTGGGTGUAGGAGUUAGATGAGTGUTTURGGGXGGUAGUAGGAGUAGAATTUTGTGTGGUUUUARGGUTGTGTUTAGAAGGGGTAUTUATGAUTURGGGAGUUUUAGAGGTUATGTGTTAUAGTGUTUTTTTAGUTTTGUUATUUAUUAAUATUTTAAGTGTTAAAUAGUTUAGTGTGAUAGU159UAGGGUTGGGAGAATAGGATGGAUAGRGTTTTGUUAGAGUUTUATGGGAAGUTTUUTTTUAGGUAGUTGAAUUUATTTUAGGGGTAGGGAGUAUTGATUAGGGGTTGGGAUATTGUUURGGGAGGAGGATGAGGATGTTTUUAGGUUTXGGUTGAUTUATGGTAGTGAGTATTAGTUAUTUUUTUAUAAGAATUAGUUUAUATUUTUTAGTAGUUTUTTGTUTUUUAGAGGUUUUTGUUUUATGTTTAUUTGUUTGAAGUTUUTUTUURGGURGUUUUUAUUUAUATURGUAUAGTTTGG160UAAAUTGTGRGGATGTGGGTGGGGGRGGURGGGAGAGGAGUTTUAGGUAGGTAAAUATGGGGUAGGGGUUTUTGGGAGAUAAGAGGUTAUTAGAGGATGTGGGUTGATTUTTGTGAGGGAGTGAUTAATAUTUAUTAUUATGAGTUAGUXGAGGUUTGGAAAUATUUTUATUUTUUTUURGGGGUAATGTUUUAAUUUUTGATUAGTGUTUUUTAUUUUTGAAATGGGTTUAGUTGUUTGAAAGGAAGUTTUUUATGAGGUTUTGGUAAAARGUTGTUUATUUTATTUTUUUAGUUUTGU161GAGGAUTAAAAGAAGUUAGAGATGUTGGTUAATTGAUAUAAAAATAAAGAGUTAAGGGAGAGGTTGAGAGAGGGAGAGUAATATUTATGGGTGTUTGGAATTTTTAAAGGGUTUAGAGGAGGAGGGGGURGGGRGTGGTGGUTUAXGUUTGTTATUXGAGUAUTTTGGGAGGUUAAGGTGGGUAAATUARGAGGTUAGGAGTTTGAGAGUAGUUTGAUUAAUATGGTGUAAUUURGTUTUTAUTAAAAATAUAAAATTTAGURGGGTGTGGTTGTGTGUUTGTAATUUUAGUTAUTUAGG162UUTGAGTAGUTGGGATTAUAGGUAUAUAAUUAUAUURGGUTAAATTTTGTATTTTTAGTAGAGARGGGGTTGUAUUATGTTGGTUAGGUTGUTUTUAAAUTUUTGAUUTRGTGATTTGUUUAUUTTGGUUTUUUAAAGTGUTXGGATAAUAGGXGTGAGUUAUUARGUURGGUUUUUTUUTUUTUTGAGUUUTTTAAAAATTUUAGAUAUUUATAGATATTGUTUTUUUTUTUTUAAUUTUTUUUTTAGUTUTTTATTTTTGTGTUAATTGAUUAGUATUTUTGGUTTUTTTTAGTUUTU163UUAGGAGUURGUUTGGGAGRGRGUAGRGUTUTAGGAGURGAGAGURGUTGUTTGGUUUTRGUTGGURGGGTAAAURGAGGGGAAGUTUUTGGUUTUUTTTUUUTTAAGUUUUTTATTGUTTUTGTGGGGAAGGUUUTUUTAGGTAGAGGXGAAGGAURGGGGAGATAAUUTUTUUUATGGGUUAUATURGUTGUUATGGTUTGTGTRGTGUUAGAAGGTAUUTUTUAGUUUTUAGTGURGTGAAAAATUTGAUAUTUAAGAAGGTRGATTGAUARGUUTAARGTRGUAUAGUAATTTAGT164AUTAAATTGUTGTGRGARGTTAGGRGTGTUAATRGAUUTTUTTGAGTGTUAGATTTTTUARGGUAUTGAGGGUTGAGAGGTAUUTTUTGGUARGAUAUAGAUUATGGUAGRGGATGTGGUUUATGGGAGAGGTTATUTUUURGGTUUTTXGUUTUTAUUTAGGAGGGUUTTUUUUAUAGAAGUAATAAGGGGUTTAAGGGAAAGGAGGUUAGGAGUTTUUUUTRGGTTTAUURGGUUAGRGAGGGUUAAGUAGRGGUTUTRGGUTUUTAGAGRGUTGRGRGUTUUUAGGRGGGUTUUTGG165GAGGUARGAAGUTGURGGAGUTAUTUAGUTTTAUUTUTAGGAAAGATAUAGRGAATUAURGUUAATAAAAUAAAGUAAAAUAAAAAGUTRGUUATGUTGAARGGAATGGGAAAATTGUTUTUTTGTUAUTAATTTTGATTGAATTGAGTXGGUAATUTUTGAAURGGTTUAUTGATAUAAUAATAGGAAAUATTTAAUTGTTTUTTGUAUUTTTAAAUATAAATAGTAGGTTTTTAAGUAGTUAGTAGGRGATGTGTGATUAAGGTTUAGAUAGARGUAGAUAAUTGATUAUUUAUTUAG166UTGAGTGGGTGATUAGTTGTUTGRGTUTGTUTGAAUUTTGATUAUAUATRGUUTAUTGAUTGUTTAAAAAUUTAUTATTTATGTTTAAAGGTGUAAGAAAUAGTTAAATGTTTUUTATTGTTGTATUAGTGAAURGGTTUAGAGATTGUXGAUTUAATTUAATUAAAATTAGTGAUAAGAGAGUAATTTTUUUATTURGTTUAGUATGGRGAGUTTTTTGTTTTGUTTTGTTTTATTGGRGGTGATTRGUTGTATUTTTUUTAGAGGTAAAGUTGAGTAGUTURGGUAGUTTRGTGUUT167GAUUTUAGUTURGGGTGAUAURGGTGGGRGTRGGGTGTGGUUTUAGAUAGUTUUUTTUUTUUURGGUTGGTTGUUAGGTUAAUAURGGGTGGGAUTAGUUTUTGGTGTRGGUAGTAGUUUUATGUTUURGGUUTTTGGGTTUTTGUATGXGURGTUUUUATUAUUTGGUTGUUUUTUTUAUTTURGTUTUUAUUTGTUURGGGTUAUUTGTUUTTUAAGUUAGAAATTAAGGAUAGUAUUUUUTUUUAGAURGUUTGGUTGUAGTUURGGGATGGGRGUTUUTAGTRGUUTAGATRGGGU168GUURGATUTAGGRGAUTAGGAGRGUUUATUURGGGAUTGUAGUUAGGRGGTUTGGGAGGGGGTGUTGTUUTTAATTTUTGGUTTGAAGGAUAGGTGAUURGGGAUAGGTGGAGARGGAAGTGAGAGGGGUAGUUAGGTGATGGGGARGGXGUATGUAAGAAUUUAAAGGURGGGAGUATGGGGUTAUTGURGAUAUUAGAGGUTAGTUUUAUURGGTGTTGAUUTGGUAAUUAGURGGGGAGGAAGGGAGUTGTUTGAGGUUAUAUURGARGUUUAURGGTGTUAUURGGAGUTGAGGTU169GTATUTGTGTUAAUUAGRGGTTUTUAGUUTGGUUTUATUUAGGGUUTGAAGUUTAUTAUAGAAUUUUUAGUAGUARGTGGGGTGUAUAGUAAAGATUAGUUUTGGAUAUAGURGGGTGUTUAGGGRGGGGTGAGGGGGUAGGAGGUAGGAXGUAGGAGGTGAGUTGTURGGGRGGGGUAGGATGAGGGAGTUUTGUATTGUAGAGUTAAGGGGGAGAATUATUAGUAUUUTAATTAGUTUTTGATGGUTTUUAAAGUUTTTTAAGTUUTTTTTTTTTTTTTTTTTTTTTATUUUTAUAAG170UTTGTAGGGATAAAAAAAAAAAAAAAAAAAAAGGAUTTAAAAGGUTTTGGAAGUUATUAAGAGUTAATTAGGGTGUTGATGATTUTUUUUUTTAGUTUTGUAATGUAGGAUTUUUTUATUUTGUUURGUURGGAUAGUTUAUUTUUTGXGTUUTGUUTUUTGUUUUUTUAUUURGUUUTGAGUAUURGGUTGTGTUUAGGGUTGATUTTTGUTGTGUAUUUUARGTGUTGUTGGGGGTTUTGTAGTAGGUTTUAGGUUUTGGATGAGGUUAGGUTGAGAAURGUTGGTTGAUAUAGATAU171GATTAAUTTGUUTUUTGAUAAGTUATAUUUTTTAGUTTAGTAUTAAGGUAGAAGAGAGUUUTGTTGAAGAGUURGUTTGTGTTUTGTGGTAAAGAUAUAGGUUTAURGGUTTUTUXGTGGGTUUUAGTGUTGAGAAGGGUAUAGGUTGGUTGGAGAUAGTGUUUTGUTTGAUAGAUUUUTUUAXGUTRGGATUUTTUUAGTUTGUAURGGUUAUUTGUAUTGGTTTUARGGAAGAGUTAGAATTUTGTTTTAATGTTGGUUAGTTTUUATUATTAGUTTGAAAAGAAUAUAGAAUTTARG172RGTAAGTTUTGTGTTUTTTTUAAGUTAATGATGGAAAUTGGUUAAUATTAAAAUAGAATTUTAGUTUTTURGTGAAAUUAGTGUAGGTGGURGGTGUAGAUTGGAAGGATURGAGXGTGGAGGGGTUTGTUAAGUAGGGUAUTGTUTUUAGUUAGUUTGTGUUUTTUTUAGUAUTGGGAUUUAXGGAGAAGURGGTAGGUUTGTGTUTTTAUUAUAGAAUAUAAGRGGGUTUTTUAAUAGGGUTUTUTTUTGUUTTAGTAUTAAGUTAAAGGGTATGAUTTGTUAGGAGGUAAGTTAATU173GAUUAUAGGTGTGTGUTATUATGUURGGGTAATTTTTATATTTTTTGGTUTUAUTATGTTGUUUAGGUTGGTUTUAAAUTUUTGGGUTUAAGTGATUUTUUTGUUTUAGUUTUUUAAAGTGTTGGATTAGAGGUATGAGUUAUUTTGUAXGTTTGUUTUUTGAUUTUAGGTUUUUARGGAGTTGGTUATUTTUTGGGUUTRGUTUAGURGGTGUTGAAGGTGAGTUATGUTRGATGATGAUUTGAGGAGUAGAAGAAGGTGUAGGTGAGTUAUUTGAGGGGAAUTGGGTUATGAUUAGAG174UTUTGGTUATGAUUUAGTTUUUUTUAGGTGAUTUAUUTGUAUUTTUTTUTGUTUUTUAGGTUATUATRGAGUATGAUTUAUUTTUAGUAURGGUTGAGRGAGGUUUAGAAGATGAUUAAUTURGTGGGGAUUTGAGGTUAGGAGGUAAAXGTGUAAGGTGGUTUATGUUTUTAATUUAAUAUTTTGGGAGGUTGAGGUAGGAGGATUAUTTGAGUUUAGGAGTTTGAGAUUAGUUTGGGUAAUATAGTGAGAUUAAAAAATATAAAAATTAUURGGGUATGATAGUAUAUAUUTGTGGTU175AGGAAGTRGAGGUTTAGAAGTTGGGTGAUTTGTUAAAGGTRGUUAUUUARGGTGAGGGUUAGGTTUTGGGAGGGUTGAGGGGUAGGUATGGTGAGUUAGTTURGGGUATGAGGUAAGGRGTGGUAGGUUTGGGGGUAAAAGUUAUAGUUXGTGTGGAGGGGGTGGGGGGATRGAGGUUTTTGGGAAGUUTGTGGATTUTGGUTGUAGTGTGGGTGTGAUAUTGAGTGUTURGGGGAUTURGAGTTATUAUUUAGGUAUTGGUUAGUUUUARGUTUUUTUUTUUAGGTAUTTGGUTUUUTG176AGGGAGUUAAGTAUUTGGAGGAGGGAGRGTGGGGUTGGUUAGTGUUTGGGTGATAAUTRGGAGTUUURGGAGUAUTUAGTGTUAUAUUUAUAUTGUAGUUAGAATUUAUAGGUTTUUUAAAGGUUTRGATUUUUUUAUUUUUTUUAUAXGGGUTGTGGUTTTTGUUUUUAGGUUTGUUARGUUTTGUUTUATGUURGGAAUTGGUTUAUUATGUUTGUUUUTUAGUUUTUUUAGAAUUTGGUUUTUAURGTGGGTGGRGAUUTTTGAUAAGTUAUUUAAUTTUTAAGUUTRGAUTTUUTU177AGUUARGGRGAUUAUUAGGTUUATUUTUUUUUAUUTUUTUUTUUTGUAGGTGGUUTTUTGGUUAGTGTGUUTGAGTGUTUAUUTUTTGUTUTAGTGTUUTGGTGUTURGGUTUTUUTUTTUUTUUTUAUTUTUUTGGGUUTGGGUUTGUXGUTUURGGGUUTUUAGGTUTAGAUAUAAGGGTTGAATGAUUAGAUTGUTGGTUTGTTUAGTTTUUATGTGGUUTRGGUUUAUUUUAGUTUTGGUTGUUTUUUUAAAGTUTUAATUARGARGAGATUATAUAGTAAUTUTGUUUUUTUUUT178AGGGAGGGGGUAGAGTTAUTGTATGATUTRGTRGTGATTGAGAUTTTGGGGAGGUAGUUAGAGUTGGGGTGGGURGAGGUUAUATGGAAAUTGAAUAGAUUAGUAGTUTGGTUATTUAAUUUTTGTGTUTAGAUUTGGAGGUURGGGAGXGGUAGGUUUAGGUUUAGGAGAGTGAGGAGGAAGAGGAGAGURGGAGUAUUAGGAUAUTAGAGUAAGAGGTGAGUAUTUAGGUAUAUTGGUUAGAAGGUUAUUTGUAGGAGGAGGAGGTGGGGGAGGATGGAUUTGGTGGTRGURGTGGUT179AAGGTGAATGUTGUAAUUUTUTUTUUTUAGUUUTGUAGURGATUUUTGAUATAAAUTUUTTGAAGTTUAGTGGUUTUTTTUUATGUAUUTAUUAUUTAUAUUTGUTGUTTTUAAAGAAAUUAUAAUUTGGAURGGGAAUAGAAUTGGAXGTGUUAAAATGUUTGAGGAUAUTTUATXGAATGTGGUTGGUTTGATGGGAAGUTGGUATGAUTAGAAATGTUAGGAGTUTTUUUTUTXGAGGTTTUAAGUTTTGTGTTTUTGAUTUAATGGTURGGATTGAGATUAGATGAGTUAAGTTUA180GAAUTTGAUTUATUTGATUTUAATURGGAUUATTGAGTUAGAAAUAUAAAGUTTGAAAUUTXGAGAGGGAAGAUTUUTGAUATTTUTAGTUATGUUAGUTTUUUATUAAGUUAGUUAUATTXGATGAAGTGTUUTUAGGUATTTTGGUAXGTUUAGTTUTGTTUURGGTUUAGGTTGTGGTTTUTTTGAAAGUAGUAGGTGTAGGTGGTAGGTGUATGGAAAGAGGUUAUTGAAUTTUAAGGAGTTTATGTUAGGGATRGGUTGUAGGGUTGAGGAGAGAGGGTTGUAGUATTUAUUTTU181UAGUUUTGUAGURGATUUUTGAUATAAAUTUUTTGAAGTTUAGTGGUUTUTTTUUATGUAUUTAUUAUUTAUAUUTGUTGUTTTUAAAGAAAUUAUAAUUTGGAURGGGAAUAGAAUTGGAXGTGUUAAAATGUUTGAGGAUAUTTUATXGAATGTGGUTGGUTTGATGGGAAGUTGGUATGAUTAGAAATGTUAGGAGTUTTUUUTUTXGAGGTTTUAAGUTTTGTGTTTUTGAUTUAATGGTURGGATTGAGATUAGATGAGTUAAGTTUAGATGAUUATGUAAAUUTTTAGATGGGG182UUUUATUTAAAGGTTTGUATGGTUATUTGAAUTTGAUTUATUTGATUTUAATURGGAUUATTGAGTUAGAAAUAUAAAGUTTGAAAUUTXGAGAGGGAAGAUTUUTGAUATTTUTAGTUATGUUAGUTTUUUATUAAGUUAGUUAUATTXGATGAAGTGTUUTUAGGUATTTTGGUAXGTUUAGTTUTGTTUURGGTUUAGGTTGTGGTTTUTTTGAAAGUAGUAGGTGTAGGTGGTAGGTGUATGGAAAGAGGUUAUTGAAUTTUAAGGAGTTTATGTUAGGGATRGGUTGUAGGGUTG183UUTAUUAUUTAUAUUTGUTGUTTTUAAAGAAAUUAUAAUUTGGAURGGGAAUAGAAUTGGAXGTGUUAAAATGUUTGAGGAUAUTTUATXGAATGTGGUTGGUTTGATGGGAAGUTGGUATGAUTAGAAATGTUAGGAGTUTTUUUTUTXGAGGTTTUAAGUTTTGTGTTTUTGAUTUAATGGTURGGATTGAGATUAGATGAGTUAAGTTUAGATGAUUATGUAAAUUTTTAGATGGGGUUTAAAAUUAAATUTGTGTTUTUAAAUUATTUUAAATGTGTTUATUAUUAGTTATAGTTT184AAAUTATAAUTGGTGATGAAUAUATTTGGAATGGTTTGAGAAUAUAGATTTGGTTTTAGGUUUUATUTAAAGGTTTGUATGGTUATUTGAAUTTGAUTUATUTGATUTUAATURGGAUUATTGAGTUAGAAAUAUAAAGUTTGAAAUUTXGAGAGGGAAGAUTUUTGAUATTTUTAGTUATGUUAGUTTUUUATUAAGUUAGUUAUATTXGATGAAGTGTUUTUAGGUATTTTGGUAXGTUUAGTTUTGTTUURGGTUUAGGTTGTGGTTTUTTTGAAAGUAGUAGGTGTAGGTGGTAGG185GAGAGGGGAAGGGGURGAUUAUUTGUTUURGAGUUATTUTRGGGUTRGGUUAGUUATTGGGUTGGGAAUUTGTUAATUUTGGTTGATUTTUUAATGAGUTGTGAAUTGGTUTTURGGGAGGAUTTAUAGGAGGUTGGAAARGGGGUUTGGXGRGRGUTTUUUTUTUAGTGRGAGGUTGAUTGGTTGGAUTRGURGGGUTUTAUTGTGGGUUUUARGUTATGTTTAGARGUURGARGTGTUUUATTTTATTGAAUTRGTUUTGUUUUUUAAGTAGGGARGATTTAUUTUUATTTTUTAGAT186ATUTAGAAAATGGAGGTAAATRGTUUUTAUTTGGGGGGUAGGARGAGTTUAATAAAATGGGAUARGTRGGGRGTUTAAAUATAGRGTGGGGUUUAUAGTAGAGUURGGRGAGTUUAAUUAGTUAGUUTRGUAUTGAGAGGGAAGRGRGXGUUAGGUUURGTTTUUAGUUTUUTGTAAGTUUTUURGGAAGAUUAGTTUAUAGUTUATTGGAAGATUAAUUAGGATTGAUAGGTTUUUAGUUUAATGGUTGGURGAGUURGAGAATGGUTRGGGAGUAGGTGGTRGGUUUUTTUUUUTUTU187RGGGGGUAGGGAGUAGAUUTGAUTUAGTGGRGTUAGTGUTAUTTUAAAGRGGUAGRGUATTTUATTAAAAATUTGATGTAGAAATTAUUUTGGGUTTTGTTTTGUAAAGAGUATTTGUATAAGAAAAAATAATUAGURGGTTAATTUUUUXGTUUAUTGGUAGGAAGAGAGAUAGUUTTUAGAGAGTTTGGGAUTUTUTUATTUURGGAGAATTAAAAGUUTURGAGAUATUUATTTTAGAAGTTUTGGTUAATRGTTUTTAAAGTGRGGTUAGAAGAUUUUTTGRGTUTGAATGGTTTG188UAAAUUATTUAGARGUAAGGGGTUTTUTGAURGUAUTTTAAGAARGATTGAUUAGAAUTTUTAAAATGGATGTUTRGGAGGUTTTTAATTUTURGGGAATGAGAGAGTUUUAAAUTUTUTGAAGGUTGTUTUTUTTUUTGUUAGTGGAXGGGGGAATTAAURGGUTGATTATTTTTTUTTATGUAAATGUTUTTTGUAAAAUAAAGUUUAGGGTAATTTUTAUATUAGATTTTTAATGAAATGRGUTGURGUTTTGAAGTAGUAUTGARGUUAUTGAGTUAGGTUTGUTUUUTGUUUURG189UAGTGTTGTAGAUUTATTAATTATUAGGATAATTARGGARGGGGAAATUUAGAUAUAGATAUAATUAGTGUUUTUUTUUAUUTUUURGUAUARGUUUUTUURGGTUTUUUTGAUATUUTGGTGTGUAUTGTGTTUUUUTGUUATUTUUAXGUTGRGGUTUUTAUTAGAUUUAUUUUTGURGGTGUUAAAATGUUUAAAGGAAGGUTGAGTUATGUTUTGGUUTGUUUAGURGUAATAGTUATGUTGUAAUTUUUARGGAAAAUUTUUTTTUAUUUAUTUUAGAGGTUTGAGAUAUUUTAA190TTAGGGTGTUTUAGAUUTUTGGAGTGGGTGAAAGGAGGTTTTURGTGGGAGTTGUAGUATGAUTATTGRGGUTGGGUAGGUUAGAGUATGAUTUAGUUTTUUTTTGGGUATTTTGGUAURGGUAGGGGTGGGTUTAGTAGGAGURGUAGXGTGGAGATGGUAGGGGAAUAUAGTGUAUAUUAGGATGTUAGGGAGAURGGGAGGGGRGTGTGRGGGGAGGTGGAGGAGGGUAUTGATTGTATUTGTGTUTGGATTTUUURGTURGTAATTATUUTGATAATTAATAGGTUTAUAAUAUTG191GGAAGGAGRGAGUTTUTTTTTATAGGAGUTUUAGTTUUTRGTTTTGTTUTUTTRGGGTTATTUTUUAAAGAAAGURGGUTUTTGAGTUAGUTGGUAGGAGAGRGAGGRGAATGRGUTGGTGUTGGURGUAATGGUUURGGTTUAARGUTXGUTUUAGUTGGTUARGTUUTUAURGGGGRGGURGGRGGUUTGUUTGUUUARGUTUTGUUAGGAGUUUAGGTUAGUUUTTGUUTRGURGGGGURGGAGUURGTUUAAAATUAAUAAGTUTTTTGTGUUTUTUUTTTGGARGUTGTATAATT192AATTATAUAGRGTUUAAAGGAGAGGUAUAAAAGAUTTGTTGATTTTGGARGGGUTURGGUUURGGRGAGGUAAGGGUTGAUUTGGGUTUUTGGUAGAGRGTGGGUAGGUAGGURGURGGURGUUURGGTGAGGARGTGAUUAGUTGGAGXGAGRGTTGAAURGGGGUUATTGRGGUUAGUAUUAGRGUATTRGUUTRGUTUTUUTGUUAGUTGAUTUAAGAGURGGUTTTUTTTGGAGAATAAUURGAAGAGAAUAAAARGAGGAAUTGGAGUTUUTATAAAAAGAAGUTRGUTUUTTUU193UTGGTTGTGGAAGGAGRGAGUTUTURGTUUURGGGAGTATGUAAGTTTGGGUTGUARGATUAUTTGGAAGGGATTGGGRGGAGTTUTGTUATTTGGAGAAAGGGTUUTGGGAGUTTUAGGTTTGTGTAGGGRGAGGARGGGGRGGTTUTGXGTURGGUUAGGTTGGUUUTRGAGGAUUUAGURGTUUUUAAUUTUUTAAAUTGUTGTRGGATGTAGAAGAUTRGUATTUAUTGUTUTUUAUAGTRGGTGAAGGGAGAARGURGAAAAGGGURGUATTUUUTUUTGURGGTUUUUTUUUUT194AGGGGAGGGGAURGGUAGGAGGGAATGRGGUUUTTTTRGGRGTTUTUUUTTUAURGAUTGTGGAGAGUAGTGAATGRGAGTUTTUTAUATURGAUAGUAGTTTAGGAGGTTGGGGARGGUTGGGTUUTRGAGGGUUAAUUTGGURGGAXGUAGAAURGUUURGTUUTRGUUUTAUAUAAAUUTGAAGUTUUUAGGAUUUTTTUTUUAAATGAUAGAAUTURGUUUAATUUUTTUUAAGTGATRGTGUAGUUUAAAUTTGUATAUTUURGGGGARGGAGAGUTRGUTUUTTUUAUAAUUAG195GGGTGTUAGGUTAUUUTTGAAGGGAUUTAUUTUUTUUAGUUAUTGUUAUTGGAUUUTUUUTUAGUUUUTUTAGUAAAGUAGUUUUAATGUATGTUUTGAGATTGTUURGGAAAAUTGTUAUTUAGAGGGGAAGAUTUTTGGGUAUAGAGUXGTTATTTATAAUAGUAAGAUAUTGUAGGUTGUUTAAAUAUTUUARGAUAGAGATGARGGAGUAATTUARGGUAUUUUTGUUAAGAGAGTATTAUAUAGUUATTAAAAATGATUAAGUAGAGAURGGTAGTGARGUTGAGTAATGTTTTU196GAAAAUATTAUTUAGRGTUAUTAURGGTUTUTGUTTGATUATTTTTAATGGUTGTGTAATAUTUTUTTGGUAGGGGTGURGTGAATTGUTURGTUATUTUTGTRGTGGAGTGTTTAGGUAGUUTGUAGTGTUTTGUTGTTATAAATAAXGGUTUTGTGUUUAAGAGTUTTUUUUTUTGAGTGAUAGTTTTURGGGAUAATUTUAGGAUATGUATTGGGGUTGUTTTGUTAGAGGGGUTGAGGGAGGGTUUAGTGGUAGTGGUTGGAGGAGGTAGGTUUUTTUAAGGGTAGUUTGAUAUUU197GUUUAURGRGGAGGGUUUUUUTATUUTUUTUATUUTUAUTGGUTUAUUUAGGGUAUUAUUAUUTUUTUUAGGAAAUUUTUUUTGUUUUUTATUTUTGGGTGTUTUAUAUUUTGGGUAUUTAUAGUUAGAAUUUUAUUTURGGGUUUTUXGTTTUUAGTGGUTGAGTAGGAGUTTUAGTTTTAGGAGAUTUUUUTGAGUAGAAURGAUUUUTUTTUATUTTUUUAAUUUUUAUUUAUAUAUTUAGGAUTGGGTAURGGGGUUTGUUUUAATTTGUAGGUTTAGAGTUAGGGGTTAGGGTGG198UAUUUTAAUUUUTGAUTUTAAGUUTGUAAATTGGGGUAGGUUURGGTAUUUAGTUUTGAGTGTGTGGGTGGGGGTTGGGAAGATGAAGAGGGGTRGGTTUTGUTUAGGGGAGTUTUUTAAAAUTGAAGUTUUTAUTUAGUUAUTGGAAAXGGAGGGUURGGAGGTGGGGTTUTGGUTGTAGGTGUUUAGGGTGTGAGAUAUUUAGAGATAGGGGGUAGGGAGGGTTTUUTGGAGGAGGTGGTGGTGUUUTGGGTGAGUUAGTGAGGATGAGGAGGATAGGGGGGUUUTURGRGGTGGGUA199UTTAAATGAGAAGAAUATGTTTUTAUAURGUATTTGTGAAAGTTTGGUTRGGAGUTARGRGUTGATTAATATUAGATUTUUTTUAUTRGUUTRGUUAUAATUTTGTUAUATUTGGUTGAUAAATUURGAGGAAUTURGGUAAAGUUAGGXGGRGGRGGGGUTURGGGTUTGGGRGGRGGUTURGGAGGAGUAGRGGGAGAUUURGUAGRGGUUTUUTUUTTUTURGUURGRGGUUUUUAGUUTRGURGURGURGUURGGUTUUUAGUARGGAAURGARGGGGRGUTUURGAGARGGGRGA200TRGUURGTUTRGGGAGRGUUURGTRGGTTURGTGUTGGGAGURGGGRGGRGGRGGRGAGGUTGGGGGURGRGGGRGGAGAAGGAGGAGGURGUTGRGGGGTUTUURGUTGUTUUTURGGAGURGURGUUUAGAUURGGAGUUURGURGUXGUUTGGUTTTGURGGAGTTUUTRGGGATTTGTUAGUUAGATGTGAUAAGATTGTGGRGAGGRGAGTGAAGGAGATUTGATATTAATUAGRGRGTAGUTURGAGUUAAAUTTTUAUAAATGRGGTGTAGAAAUATGTTUTTUTUATTTAAG201GTGGTAGGTUTGTGTGGAGAUTTGAATUUTGTTTTUTUUUAGUUTTTTUUAUUAAGGAUAUUUAGGAGAGUAAGGATATGGUUAGAGGAGAGGTGGTGTTUUUUTUTTGAUTGGGUUUTGUTUTUAGUUUUAUAGGTGATURGGAAGATTXGGGTGGAGUAGTTTUUTGATGUUTURGGTAGUUTGAAGUTGTGGTGUUAGTTTTTUAAUATTUTTAGTGAUTUAGTUTTGAUATGGGUUAAGGATUAGRGUUUAGTGGGRGAGGTGGGUAGGAGGTAAGUUAARGAUAUUAUTGUUAUU202GGTGGUAGTGGTGTRGTTGGUTTAUUTUUTGUUUAUUTRGUUUAUTGGGRGUTGATUUTTGGUUUATGTUAAGAUTGAGTUAUTAAGAATGTTGAAAAAUTGGUAUUAUAGUTTUAGGUTAURGGAGGUATUAGGAAAUTGUTUUAUUXGAATUTTURGGATUAUUTGTGGGGUTGAGAGUAGGGUUUAGTUAAGAGGGGAAUAUUAUUTUTUUTUTGGUUATATUUTTGUTUTUUTGGGTGTUUTTGGTGGAAAAGGUTGGGAGAAAAUAGGATTUAAGTUTUUAUAUAGAUUTAUUAU203TGUUTAUUAUAUUTRGTGGGTGAAAUAGATATTTRGAGUATGAUTGAGUTTATTAAGAGUUUTGRGGRGUTTUUTUTGURGGGGGTTTAGAAATTTUAAAGGATGGGGGTTGAGGGAGGGAGGAGTTATGGGUATGTGATGTGGAUAGGGXGGGUAGGAGGATGGAAGTAAUAGGTUUAAAATGTATUTTTGGTGGUURGGUAGAGUTUTTGUATGGGGTGAGAATGGTAATTTAGGAAGAGUAAGTUTTUUUATUTGTGAAGUAGAAGAAAAAAGTGGAUTTAAGGAGAAGTTRGGGTG204UAUURGAAUTTUTUUTTAAGTUUAUTTTTTTUTTUTGUTTUAUAGATGGGAAGAUTTGUTUTTUUTAAATTAUUATTUTUAUUUUATGUAAGAGUTUTGURGGGUUAUUAAAGATAUATTTTGGAUUTGTTAUTTUUATUUTUUTGUUXGUUUTGTUUAUATUAUATGUUUATAAUTUUTUUUTUUUTUAAUUUUUATUUTTTGAAATTTUTAAAUUUURGGUAGAGGAAGRGURGUAGGGUTUTTAATAAGUTUAGTUATGUTRGAAATATUTGTTTUAUUUARGAGGTGTGGTAGGUA205GAGUUAAUUTUTUUTTTUATTUUTGGAGGTGGGGGAUURGUUUTUATUTUAGGUUTGAAGAGGGUTGTGTGTGAGTTUTUUAUTTGTGTGTGGGGTGAGUURGGUUUATGUAUAUAGUTAUAUAUAUATUAUAUAUUUAUAUURGGAUAXGRGUUTUAGGTUUUUAUAUTGUUUTTAUAUAUATGRGUUUUTUAUAUATGUATGTUUUUTTTGUAUAUARGUUUUUTRGUAUARGUATGUUUUUTRGUAUARGUATGUAUAUAGGUTUAUTUTGUTGUUTGTUUUTGGUTGUTGTGTGUT206AGUAUAUAGUAGUUAGGGAUAGGUAGUAGAGTGAGUUTGTGTGUATGRGTGTGRGAGGGGGUATGRGTGTGRGAGGGGGRGTGTGTGUAAAGGGGAUATGUATGTGTGAGGGGRGUATGTGTGTAAGGGUAGTGTGGGGAUUTGAGGRGXGTGTURGGGTGTGGGTGTGTGATGTGTGTGTAGUTGTGTGUATGGGURGGGUTUAUUUUAUAUAUAAGTGGAGAAUTUAUAUAUAGUUUTUTTUAGGUUTGAGATGAGGGRGGGTUUUUUAUUTUUAGGAATGAAAGGAGAGGTTGGUTU207UUUARGGGGGUAGGUAURGGAGGGGGTGUUUAUAGAGGATAGAGGARGURGAGAAGTGAUUTGGGGAGUUATAGGATGAGGAAGAGAGAAGAGATGAUAGUAGGGGUTGTAGGAGGTUAUUUTUUARGGAGGGAGGGGTGARGGUAGAGGXGTURGUAGGAGUTGGTAURGGTGGGGUTGUUUUUAGGGGGGGUTGAUAGAGGUAGUAAUTGAGUAGGUAGGGGTGGAGRGAGGTGUUAGUUTGURGTGGAAAGGAGARGUUAGUAGRGGGGGGUUUTUUTGGGGTUUUAGTUUTGUTUT208AGAGUAGGAUTGGGAUUUUAGGAGGGUUUUURGUTGUTGGRGTUTUUTTTUUARGGUAGGUTGGUAUUTRGUTUUAUUUUTGUUTGUTUAGTTGUTGUUTUTGTUAGUUUUUUUTGGGGGUAGUUUUAURGGTAUUAGUTUUTGRGGAXGUUTUTGURGTUAUUUUTUUUTURGTGGAGGGTGAUUTUUTAUAGUUUUTGUTGTUATUTUTTUTUTUTTUUTUATUUTATGGUTUUUUAGGTUAUTTUTRGGRGTUUTUTATUUTUTGTGGGUAUUUUUTURGGTGUUTGUUUURGTGGG209TGAUAUTUAGGATUUAAAAGUTAGUUUTGUUUAUUUUAGUUUUTGGAUUTGUTTAUUTGGGTGTGUAUUTGUTURGGGGGGTGGAGGTGUTUUUUAUAGTURGGGUUAGGAUAGUUTUAGGGGAGAGTGAAGGUUTGUAGGAGGGUAGGXGAGAUAAGGAGGGTGTUUAGGGUTAGGGAGTGURGGATGAAAUUAGUTUTGTUUUTGTGUAGGUTUUAGGUTUURGUUTGAUAAAUAGGUAGGGAGUUAUAGTUAGGGAUAATAAAAAUTTGGTGUAUTUTGAAAGUAGUAUTTGGAUAG210TGTUUAAGTGUTGUTTTUAGAGTGUAUUAAGTTTTTATTGTUUUTGAUTGTGGUTUUUTGUUTGTTTGTUAGGRGGGAGUUTGGAGUUTGUAUAGGGAUAGAGUTGGTTTUATURGGUAUTUUUTAGUUUTGGAUAUUUTUUTTGTUTXGUUTGUUUTUUTGUAGGUUTTUAUTUTUUUUTGAGGUTGTUUTGGUURGGAUTGTGGGGAGUAUUTUUAUUUUURGGAGUAGGTGUAUAUUUAGGTAAGUAGGTUUAGGGGUTGGGGTGGGUAGGGUTAGUTTTTGGATUUTGAGTGTUAU211UAAATAAGTAGTTAUUTUAGAAGTUAUTTARGTAAAAGAUTUATTUUUUAAAARGUUAGGUAUATGGATTATUAUTGTGTTATTUAARGARGATAUAATGGUAUAGAATGTATUATAUTGAGAAGTGAGTGUUUTUTURGGGAUATAUTXGTUAGTGAGTUATUUAGUAUTAGAAUAUTGGAGATATAAATAAATAUUAUUTUTTUTAAAAUAGTUTGAAATTUAAGTGGTUATAAUUTAGAGUATUATGGURGGGUATGGTGGUTUATGUUTGTAAUUUUAGUATGAGGUTGAGATGGG212UUATUTUAGUUTUATGUTGGGGTTAUAGGUATGAGUUAUUATGUURGGUUATGATGUTUTAGGTTATGAUUAUTTGAATTTUAGAUTGTTTTAGAAGAGGTGGTATTTATTTATATUTUUAGTGTTUTAGTGUTGGATGAUTUAUTGAXGAGTATGTUURGGAGAGGGUAUTUAUTTUTUAGTATGATAUATTUTGTGUUATTGTATRGTRGTTGAATAAUAUAGTGATAATUUATGTGUUTGGRGTTTTGGGGAATGAGTUTTTTARGTAAGTGAUTTUTGAGGTAAUTAUTTATTTGA213GTUUTUAUATTTGAUTURGGATAAAUUTUTTUAAATATTTTAUAGAUTUTGGUTTTUTRGTTAAUAAGUAGUTUAUAUATATAGTGTUTUAGUAGTGAUAGATGUTGGUUUAUUURGAGGTUAGGATGAUTUAGUAGGGATTGAGTTTGXGGGRGTUATGUTUUAAGGUURGGAATAGGAGGTTGGTGUTUATTUUTUAUATAGTGGGUAAATUUTAGGGUAGGGGAGGGGGGGUAATGUUAGAGAATGGTUUUUAUUTGGGGRGGTUTGARGGUUAGAGATGUAGAGAAAGAGARGUUT214AGGRGTUTUTTTUTUTGUATUTUTGGURGTUAGAURGUUUUAGGTGGGGAUUATTUTUTGGUATTGUUUUUUUTUUUUTGUUUTAGGATTTGUUUAUTATGTGAGGAATGAGUAUUAAUUTUUTATTURGGGUUTTGGAGUATGARGUUXGUAAAUTUAATUUUTGUTGAGTUATUUTGAUUTRGGGGTGGGUUAGUATUTGTUAUTGUTGAGAUAUTATATGTGTGAGUTGUTTGTTAARGAGAAAGUUAGAGTUTGTAAAATATTTGAAGAGGTTTATURGGAGTUAAATGTGAGGAU215GAAAGUAGUUUTUTUUUTGUUUTGTAAGGTGATUUURGATURGGGAATTUUUAUTTUTGAAGGARGTTUTGGAAAAGTGUAUAGATTAAUTGAGATTUUTGUTTUTGGATUAAGUAUTUUTGAUAUTATXGTTURGATTTTUTAAAAAAGAGATTGTGGUAAAATUTAUUTXGTGAGATUAGAAAATGUAGUAGGGATGAATUAURGGUUUTUTUAGAUUTUAUUAGUUTUUAGGUUATTUUTAAGAGUUTUAUTUUTURGTTUTGTTGGUAGTGGGGGAGGTARGGGGURGGATGGUA216TGUUATURGGUUURGTAUUTUUUUUAUTGUUAAUAGAARGGAGGAGTGAGGUTUTTAGGAATGGUUTGGAGGUTGGTGAGGTUTGAGAGGGURGGTGATTUATUUUTGUTGUATTTTUTGATUTUAUXGAGGTAGATTTTGUUAUAATUTUTTTTTTAGAAAATRGGAAXGATAGTGTUAGGAGTGUTTGATUUAGAAGUAGGAATUTUAGTTAATUTGTGUAUTTTTUUAGAARGTUUTTUAGAAGTGGGAATTUURGGATRGGGGATUAUUTTAUAGGGUAGGGAGAGGGUTGUTTTU217AAGAAAAGAGAAAGUUUATUUAGGTAAGGGUAGUUTGGTGAUTATTAUUUTGGGGAGAUTUUUUAUUUAUAUTGUUAUTUUAGGUTUAUURGAGGGUTGUAGUTTUUTURGGATGGATUUAGGGXGGUTAUTGGTUUUAGAGUTGGGGGUTGAGTGGGUURGTGUXGAGGGUTGTGGXGTUTGAUAAGURGGUTUUUAUTGTGAGUAGGGAAGGGRGGATGGGRGGGGGUUARGGUTGUUUTGGUTUUUUAUUUTGUTGTGUTTUTUTUTAUTUUUUTGUUUTGUUTUUTAAUAUUUAGT218AUTGGGTGTTAGGAGGUAGGGUAGGGGAGTAGAGAGAAGUAUAGUAGGGTGGGGAGUUAGGGUAGURGTGGUUUURGUUUATURGUUUTTUUUTGUTUAUAGTGGGAGURGGUTTGTUAGAXGUUAUAGUUUTXGGUARGGGUUUAUTUAGUUUUUAGUTUTGGGAUUAGTAGUXGUUUTGGATUUATURGGAGGAAGUTGUAGUUUTRGGGTGAGUUTGGAGTGGUAGTGTGGGTGGGGAGTUTUUUUAGGGTAATAGTUAUUAGGUTGUUUTTAUUTGGATGGGUTTTUTUTTTTUTT219UTGAGGUAGGGUTGUAGGUTUAGGAGGAGGAGATGGGTGGAGAGAGAAUAAGUTUAUUURGGGAGGGTGAUTAUAGGAGAAATGGGUUUUTUAAGTATGUTGATTTUXGUUTUAUTGUTGUUTGUTUTTUXGUUUAUUTURGGUTUTGGUTUATUTGUTUTTGTAAGUAGGGTUUTGGGUTGGGTGUTGUAGGXGUATGAGGAAAGTGGGAGURGGGARGGGGUAGUTUAGGGUARGUUUTUUAAUAUTGRGUTURGAGGAUUTUAGRGGTTTTAUTUAGGGGTGUUAUTGAGGUAUAGU220GUTGTGUUTUAGTGGUAUUUUTGAGTAAAAURGUTGAGGTUUTRGGAGRGUAGTGTTGGAGGGRGTGUUUTGAGUTGUUURGTUURGGUTUUUAUTTTUUTUATGXGUUTGUAGUAUUUAGUUUAGGAUUUTGUTTAUAAGAGUAGATGAGUUAGAGURGGAGGTGGGXGGAAGAGUAGGUAGUAGTGAGGXGGAAATUAGUATAUTTGAGGGGUUUATTTUTUUTGTAGTUAUUUTUURGGGGTGAGUTTGTTUTUTUTUUAUUUATUTUUTUUTUUTGAGUUTGUAGUUUTGUUTUAG221GUUUAGGUTGGAGTGUAGTGGRGTGATUTTGGUTUAUTGUAAUUTUTGUUTUURGGGTTUAAGRGATTUTUUTGUUTUAGUUTUUUAGATAUUTGGGATTAUAGGTGTGTGAUAUUATAUUUAGUTAATTTTTGTATTTTTAGTAGAGAXGGUUATGTTAGTUAGGUTGGTUTTGAAUTUUTGAUUTUAGTGATTUAURGGUUTUAGUUUUUAAAGTGUTGGTATTATAGTUATGAGUUAUTGUAUURGGUUTUTGUTTTTGUTTUUTTAGTGGUATUUUAUTGUUTTGUTTTUAAUATT222AATGTTGAAAGUAAGGUAGTGGGATGUUAUTAAGGAAGUAAAAGUAGAGGURGGGTGUAGTGGUTUATGAUTATAATAUUAGUAUTTTGGGGGUTGAGGURGGTGAATUAUTGAGGTUAGGAGTTUAAGAUUAGUUTGAUTAAUATGGUXGTUTUTAUTAAAAATAUAAAAATTAGUTGGGTATGGTGTUAUAUAUUTGTAATUUUAGGTATUTGGGAGGUTGAGGUAGGAGAATRGUTTGAAUURGGGAGGUAGAGGTTGUAGTGAGUUAAGATUARGUUAUTGUAUTUUAGUUTGGGU223GUUAUTUTATAAAAATGAAGAGUAGAGUTRGAGTGUTTATAAUARGTUATTTTTAUUUAAGAUAGAGAAGAAAAARGAAAGAGAGUUTGAGUATTUUTTTGAUTUUUTUUAUUUURGGAAGGTATATTUAGAGTUTUUAAGAUTGUUTUXGUUUAUTUAUATGTTTATGGUURGGTGAGAURGUATUUTUUUTTTUTATATUTGTUUUTTTTUTGGATGUAGGGAUAUAGAATUUUUTAAGTGGGAAGAGUTTTGGAGTGGAGGUTGTTUAAAGTTUTGTGGTGATTAATTATTAUUTAU224TAGGTAATAATTAATUAUUAUAGAAUTTTGAAUAGUUTUUAUTUUAAAGUTUTTUUUAUTTAGGGGATTUTGTGTUUUTGUATUUAGAAAAGGGAUAGATATAGAAAGGGAGGATGRGGTUTUAURGGGUUATAAAUATGTGAGTGGGXGGAGGUAGTUTTGGAGAUTUTGAATATAUUTTURGGGGGTGGAGGGAGTUAAAGGAATGUTUAGGUTUTUTTTRGTTTTTUTTUTUTGTUTTGGGTAAAAATGARGTGTTATAAGUAUTRGAGUTUTGUTUTTUATTTTTATAGAGTGGUT225ATTAAAAUAGUAAAUTUUAGGUUUAAAGTAGGTTTUAGTUTUTATTAAGATAAUAAAAGGTUUTAAATGUUAGGUUTGGGRGUAAAUTGTGUAGAUAAGRGGGTGGURGGAGAAGGAGGGGGGTUAAGGAAGAGAGGGAAAUTUAATTGAXGGTTAUTTTTTTTTUAGAGTTATTTURGGTGGGTUTGUUUUUAUUUUTUAAUAAATTTTGTTGUTUTGAGUATTUUAGGUATAAAAAGTGAGGUUUTGGAGGGUUUUTGAGAUUAGRGTUUTGUAUAGTGAUATGGUAUAGTGAUATGG226UUATGTUAUTGTGUUATGTUAUTGTGUAGGARGUTGGTUTUAGGGGUUUTUUAGGGUUTUAUTTTTTATGUUTGGAATGUTUAGAGUAAUAAAATTTGTTGAGGGGTGGGGGUAGAUUUAURGGAAATAAUTUTGAAAAAAAAGTAAUXGTUAATTGAGTTTUUUTUTUTTUUTTGAUUUUUUTUUTTUTURGGUUAUURGUTTGTUTGUAUAGTTTGRGUUUAGGUUTGGUATTTAGGAUUTTTTGTTATUTTAATAGAGAUTGAAAUUTAUTTTGGGUUTGGAGTTTGUTGTTTTAAT227GGUTUTGAGAGTGUTGGAAUUAAURGGARGGGGTUAGUUUUAUUATGGGAUUTGGURGATGAGTUATUTUTUTGAAGGRGTUTTUUUTTUTGTGAAGTGGGGAAGGTAAUTGTUATUUUAUAGGGRGATTGTGGGUAUURGGGAGAUUXGUTGAGGGATGUTGUAGTGTAGAAGUTTUUUAAATUTARGUTGUTTUTUTTUUTUUTUAGTUUTUTUURGUTGUTGUUUTURGGTTUATGUUUTGTGGUTGATUUATUAURGGUTUTUUARGGUUTTUAUUTTGGGRGGGTTGGATGGUTG228AGUUATUUAAUURGUUUAAGGTGAAGGURGTGGAGAGURGGTGATGGATUAGUUAUAGGGUATGAAURGGAGGGUAGUAGRGGGAGAGGAUTGAGGAGGAAGAGAAGUAGRGTAGATTTGGGAAGUTTUTAUAUTGUAGUATUUUTUAGXGGGTUTUURGGGTGUUUAUAATRGUUUTGTGGGATGAUAGTTAUUTTUUUUAUTTUAUAGAAGGGAAGARGUUTTUAGAGAGATGAUTUATRGGUUAGGTUUUATGGTGGGGUTGAUUURGTURGGTTGGTTUUAGUAUTUTUAGAGUUU229GURGURGUTTTTUUAGTUTTGUUUAAUURGGTATTTUTGRGUTTGUUTUAGUUAUURGUAGGAGRGUAGGURGUUUTTRGTUUTUURGTUUTUTGRGUUUAUAGGAUUURGGGUUURGUUUAGTURGUAGGTUURGUAGGTUUUUURGGGXGTGTUTTUUTGGUUUTGRGAUUUURGGGAUAGRGUTGAGAAUARGRGGAAGGTGGGGAGARGRGRGGRGUTGGURGGGTUUUTGGRGURGTTUTRGRGGTGUAGUUTGTGUUTGGGAGTURGGURGTUUUAUUTUAGAAUUAGAGUAAA230TTTGUTUTGGTTUTGAGGTGGGARGGURGGAUTUUUAGGUAUAGGUTGUAURGRGAGAARGGRGUUAGGGAUURGGUUAGRGURGRGRGTUTUUUUAUUTTURGRGTGTTUTUAGRGUTGTUURGGGGGTRGUAGGGUUAGGAAGAUAXGUURGGGGGGAUUTGRGGGAUUTGRGGAUTGGGRGGGGUURGGGGTUUTGTGGGRGUAGAGGARGGGAGGARGAAGGGRGGUUTGRGUTUUTGRGGGTGGUTGAGGUAAGRGUAGAAATAURGGGTTGGGUAAGAUTGGAAAAGRGGRGGU231UUTGGGAUAGGUTUAATGGAGGUTGUAGGGUUATUAGURGAUTUUTARGUAGGUTUAGTUAGUAGUUUUUTGGUUAGUUUUAUUUUTGAUTGURGGUUTUAGAAUTGGGAGUTGUTTUUTGGUAGGGUURGUUTUTGUTGGGAGAURGGAXGGTGAGTUAGUUTTAAGUURGGUAUUAGAUUUUTUTGAGGATGGAGUAGGAGUTGGUTGUUUTGAGGUTGUAAAAUTTUTTUUUTRGTGGAGAUAGGGAGGUAUUTUAGAUAUTUAUUURGGAUTUUUTTGAAUAGGGAUAGGGAGGAA232TTUUTUUUTGTUUUTGTTUAAGGGAGTURGGGGTGAGTGTUTGAGGTGUUTUUUTGTUTUUARGAGGGAAGAAGTTTTGUAGUUTUAGGGUAGUUAGUTUUTGUTUUATUUTUAGAGGGGTUTGGTGURGGGUTTAAGGUTGAUTUAUXGTURGGTUTUUUAGUAGAGGRGGGUUUTGUUAGGAAGUAGUTUUUAGTTUTGAGGURGGUAGTUAGGGGTGGGGUTGGUUAGGGGGUTGUTGAUTGAGUUTGRGTAGGAGTRGGUTGATGGUUUTGUAGUUTUUATTGAGUUTGTUUUAGG233AUAUTGTGGGGUAGGGAGGGGUATUTUTTGAGAAUAAAAGATUUATTTUTRGAUTTTUUAAAUTGGAGAGUTTUTTGAGAGAAAAGAGAGAGAUAGGTAUAGGTUUARGUUAUUUAUAUAUAGUUUTGTGUAUAUAGAURGGAUAUAGGXGTUUAUAGGUAAGTTRGUAGUTGUTUATTTTGTGAAGTGAATGUTGATTTGGGGGURGGGTGGGGTTRGTUTGTAUATRGTGUAUTGTUAGAUUUTTUUTGAAGGATTTTTGTTAUTGAAGTATUAGAAGGUUUTTGTTUTAAGGTGGTG234AUUAUUTTAGAAUAAGGGUUTTUTGATAUTTUAGTAAUAAAAATUUTTUAGGAAGGGTUTGAUAGTGUARGATGTAUAGARGAAUUUUAUURGGUUUUUAAATUAGUATTUAUTTUAUAAAATGAGUAGUTGRGAAUTTGUUTGTGGAXGUUTGTGTURGGTUTGTGTGUAUAGGGUTGTGTGTGGGTGGRGTGGAUUTGTAUUTGTUTUTUTUTTTTUTUTUAAGAAGUTUTUUAGTTTGGAAAGTRGAGAAATGGATUTTTTGTTUTUAAGAGATGUUUUTUUUTGUUUUAUAGTGTG235AUUUARGGGGAUAGGGGTUAGAGTAATGGAGTGGAAATGGUAGGTTUAUAATTTTGGUTAUAGUTGUTUUUATUTUTAAGUAAUUUAGGUTURGGGTTGGAGGGTGGRGAUUUUAAGATGRGGUUTUAGURGURGGUXGTGTTTGTGUTUUAGUXGATGAAGXGAGTGUAAAGGGUTGTAUAAARGRGAGGUAUTGAAUAAAUAUTGAGRGTGURGTUUAGATGTUURGGGGGAGGUTGAGGATUUAUAURGTGGGGAGTGUTUTGUUUUUATGGAGTGAUUTGGRGTURGUUUTUUARG236RGTGGAGGGRGGARGUUAGGTUAUTUUATGGGGGUAGAGUAUTUUUUARGGTGTGGATUUTUAGUUTUUUURGGGAUATUTGGARGGUARGUTUAGTGTTTGTTUAGTGUUTRGRGTTTGTAUAGUUUTTTGUAUTXGUTTUATXGGUTGGAGUAUAAAUAXGGURGGRGGUTGAGGURGUATUTTGGGGTRGUUAUUUTUUAAUURGGAGUUTGGGTTGUTTAGAGATGGGAGUAGUTGTAGUUAAAATTGTGAAUUTGUUATTTUUAUTUUATTAUTUTGAUUUUTGTUUURGTGGGT237RGAGGTGRGGUTGUUURGRGGUTTUUTRGGUTTUURGTUURGRGTGUTTTUUTGGAGTUUUTUUTTURGGAGGUUUTUUTGUUTUUARGTGTGUUUTTUTUUATGTUUAGUATTRGGGRGUUTUTTGTUTTTUTTUTGTTUUUTGGUTTXGGRGTUUURGGGAGTGTGAUTUURGUAGRGGGGTGUAGUTTTUUTUTGGGATGAGTGAURGGAGGGAAUURGUUTTUURGGGUARGTRGUUAGUUTUTTUUTUTTUTTUUUTAGGUTATUAAGRGGAUTTATGAUAAGAAGGRGGTGGAT238ATUUAURGUUTTUTTGTUATAAGTURGUTTGATAGUUTAGGGAAGAAGAGGAAGAGGUTGGRGARGTGUURGGGAAGGRGGGTTUUUTURGGTUAUTUATUUUAGAGGAAAGUTGUAUUURGUTGRGGGAGTUAUAUTUURGGGGARGUXGAAGUUAGGGAAUAGAAGAAAGAUAAGAGGRGUURGAATGUTGGAUATGGAGAAGGGUAUARGTGGAGGUAGGAGGGUUTURGGAAGGAGGGAUTUUAGGAAAGUARGRGGGARGGGAAGURGAGGAAGURGRGGGGUAGURGUAUUTRG239TGUAGTGTGTAUAGGAUTUUUTGAAAGGGUTUUUTGGGATGGAGGGUTTTTGGGGGGGUUTGTGGTTUTTUTUUAGUATGAGTUAUAAAUUAUATUUTUUAUAGTUAGURGGATUUAAAURGATTTGAURGAGATXGGUTUTTUAATGXGGTUTUURGGGGTGTUUURGAGGATUTGGUTGGAUTTUUAGAGTAUUTGAGUAAGAUUAGUAAGTAUUTUAURGAUTRGGAATAUAUAGGTAGAUUUTGUUUTGTGGATUUAAGGUTAGGUATUUTGTGAGUTGATAGTTAGGTGGGUTGT240UAGUUUAUUTAAUTATUAGUTUAUAGGATGUUTAGUUTTGGATUUAUAGGGUAGGGTUTAUUTGTGTATTURGAGTRGGTGAGGTAUTTGUTGGTUTTGUTUAGGTAUTUTGGAAGTUUAGUUAGATUUTRGGGGAUAUUURGGGAGAUXGUATTGAAGAGUXGATUTRGGTUAAATRGGTTTGGATURGGUTGAUTGTGGAGGATGTGGTTTGTGAUTUATGUTGGAGAAGAAUUAUAGGUUUUUUUAAAAGUUUTUUATUUUAGGGAGUUUTTTUAGGGAGTUUTGTAUAUAUTGUAU241AGGAGUUTGTGAUUUAGAAATGGTAAGTAAGGTURGATTUTUAUUAAUAAAGUAGGUATGAUUTUAGAUAAGTUUUTAUUUTGUTUTGGGUUTUAGTTTUTUUTTTAGTGAGGAGGTGGGTGAGGGTUUTGTUUTUUTURGGGAAUTGGXGATTTGGGAAGGUAGAGAUATTUUUAGAATUXGURGGAGTUUTGAAAAUAUUUARGUUUTTTGTUUUAGUAATUUTGAGAAAGGUUAUAUTGATAAAGUTGTGGGTGGUUAGATGAUAGUATTUTTGGGUUTUAGARGAAGTGGGAGGGG242UUUTUUUAUTTRGTUTGAGGUUUAAGAATGUTGTUATUTGGUUAUUUAUAGUTTTATUAGTGTGGUUTTTUTUAGGATTGUTGGGAUAAAGGGRGTGGGTGTTTTUAGGAUTURGGXGGATTUTGGGAATGTUTUTGUUTTUUUAAATXGUUAGTTUURGGAGGAGGAUAGGAUUUTUAUUUAUUTUUTUAUTAAAGGAGAAAUTGAGGUUUAGAGUAGGGTAGGGAUTTGTUTGAGGTUATGUUTGUTTTGTTGGTGAGAATRGGAUUTTAUTTAUUATTTUTGGGTUAUAGGUTUUTT243AGUUUTGGUTGAGTGUUUUUUAUTTUUUTGGUTRGAGTTUUUTGAGGAAAAAAGGTGGTGAUTUUTUUTGUAUAGAAUAAAGGUTGAGTGAGGUAUAGTGUUUAGGGGATGAGGAAGGUTGAGUURGGGAUUAGGUAGGAGGAAUUTGUXGTGUAUTUAUTUAGAUTUUTGUAGUAUURGGGGUAGGTGUTUUAUUAGRGGGUAUAGURGUTUAGURGUUTUUTUATUURGURGUAGUUAGTGGATUAUUAUAGUTGTUAGAGAGGUUUAUUAUTTGGUUAURGGGTUTARGUUTGUAGA244TUTGUAGGRGTAGAUURGGTGGUUAAGTGGTGGGUUTUTUTGAUAGUTGTGGTGATUUAUTGGUTGRGGRGGGATGAGGAGGRGGUTGAGRGGUTGTGUURGUTGGTGGAGUAUUTGUUURGGGTGUTGUAGGAGTUTGAGTGAGTGUAXGGUAGGTTUUTUUTGUUTGGTUURGGGUTUAGUUTTUUTUATUUUUTGGGUAUTGTGUUTUAUTUAGUUTTTGTTUTGTGUAGGAGGAGTUAUUAUUTTTTTTUUTUAGGGAAUTRGAGUUAGGGAAGTGGGGGGUAUTUAGUUAGGGUT245UTUTGGGUTUTUTUUAUAGGGTTGAGGUUAGAGUTATTUTUAGAATUURGURGGAGGGGUUTTGUUTGGAGGAGGGUAUAARGAUAUTTAUTTGTUUUUATUAGUTGAUUUAGGGUTGGGGTTGGGUTGGGTUAUAUAGTTUAGTGUTXGUTUTAAGAGATGTTUURGGAATAGUTGAGTUAUUTGGGUUAGGGGGTUUAUTGTGGAGAGGAGGAGGTGAGTGGGGTGGGGAGUAGGGUUUUAUUUTUUTUTUUAAGUTAAGGGUTTTTTUUTGGGTGGGUTGGGGUUAUAUUTAGGGUU246GUUUTAGGTGTGGUUUUAGUUUAUUUAGGAAAAAGUUUTTAGUTTGGAGAGGAGGGTGGGGUUUTGUTUUUUAUUUUAUTUAUUTUUTUUTUTUUAUAGTGGAUUUUUTGGUUUAGGTGAUTUAGUTATTURGGGAAUATUTUTTAGAGXGAGUAUTGAAUTGTGTGAUUUAGUUUAAUUUUAGUUUTGGGTUAGUTGATGGGGAUAAGTAAGTGTRGTTGTGUUUTUUTUUAGGUAAGGUUUUTURGGRGGGATTUTGAGAATAGUTUTGGUUTUAAUUUTGTGGAGAGAGUUUAGAGU247RGUUUTGGUTUTGGGUTTTUAUUAURGUUTGGGGUUUTGUTTGGAUTUTGUAGUTGTGTUUUAAGGUTGRGUUUTAGATTTGTUTAUTUUTTUUUUTGUUUUUTUUUTGUTTTUTUURGGUUTUTGTAGTUTTUUTGUTUUTUUAUUTAXGTGGUTGUUTTGGGUUUUATGUAGUTUUTUUUURGGGATGUUUUATGUTUTGTTUTGTGAUTGUUTTAUTUTTGATUAUUTUTGATGGUTGUTUUAGTGUAGGUAGAAUUUUUAAAGTUUTUTGTTUTUTAUATGTUUUUUTTTGUUAUU248GGTGGUAAAGGGGGAUATGTAGAGAAUAGAGGAUTTTGGGGGTTUTGUUTGUAUTGGAGUAGUUATUAGAGGTGATUAAGAGTAAGGUAGTUAUAGAAUAGAGUATGGGGUATUURGGGGGAGGAGUTGUATGGGGUUUAAGGUAGUUAXGTAGGTGGAGGAGUAGGAAGAUTAUAGAGGURGGGAGAAAGUAGGGAGGGGGUAGGGGAAGGAGTAGAUAAATUTAGGGRGUAGUUTTGGGAUAUAGUTGUAGAGTUUAAGUAGGGUUUUAGGRGGTGGTGAAAGUUUAGAGUUAGGGRG249TTTUUTUUTUTUTTTUUTTUUTTUTUUAGTTUUTUUUTTTTUUTUUTTUAUTGTTTGATTTTTAGUUUTUTGATTTTTTUTTUUTUTTUTUUAUTUTTTATTTUTTTTUATUUTUUTUURGGTUUTTTTTTUTGUTTTGTUAUUTUUTTXGTTTTUTTUTUTUTUTGGUTGAUTUAGGGGAURGGAGGTGGGUUTATUTGGAGTGAGTGAGTAAGTGTGTTGGGAGGTGAGGGTGGAGGGUTGGAGGGGGGUAGTGATUTGGUUTGAGUUUUTUUAGTATTGUTUUAGUUUUAGURGUAG250UTGRGGUTGGGGUTGGAGUAATAUTGGAGGGGUTUAGGUUAGATUAUTGUUUUUUTUUAGUUUTUUAUUUTUAUUTUUUAAUAUAUTTAUTUAUTUAUTUUAGATAGGUUUAUUTURGGTUUUUTGAGTUAGUUAGAGAGAGAAGAAAAXGAAGGAGGTGAUAAAGUAGAAAAAAGGAURGGGAGGAGGATGAAAAGAAATAAAGAGTGGAGAAGAGGAAGAAAAAATUAGAGGGUTAAAAATUAAAUAGTGAAGGAGGAAAAGGGAGGAAUTGGAGAAGGAAGGAAAGAGAGGAGGAAA251UTATAUTUTUAGGUUUAGGUUAGGGGRGGUAGUTGUUUUUUTUAUTGUUUUARGUAUAAATUUUTGGTTTUAGTUUAAAURGUTAUTGTGAGUTUUAGATUTGGGTGGGGUURGGAGUUTUUTUATTAGUAUUAGGTGGGATGGUUTTGXGAAGATAAAGUTUTGTUTGGUUUUAGUUUAGGUTGTAGUUURGGGUUUTGUUUUAGGUAGUUTGUUUAGGATGUTGTGUUAGTTTUTGAUUTTTGUUUAUTGUAGUUAGATGGGGUUATUTGTGGAGUTGGUUTTTTUTUUTTAGAATGA252TUATTUTAAGGAGAAAAGGUUAGUTUUAUAGATGGUUUUATUTGGUTGUAGTGGGUAAAGGTUAGAAAUTGGUAUAGUATUUTGGGUAGGUTGUUTGGGGUAGGGUURGGGGUTAUAGUUTGGGUTGGGGUUAGAUAGAGUTTTATUTTXGUAAGGUUATUUUAUUTGGTGUTAATGAGGAGGUTURGGGUUUUAUUUAGATUTGGAGUTUAUAGTAGRGGTTTGGAUTGAAAUUAGGGATTTGTGRGTGGGGUAGTGAGGGGGGUAGUTGURGUUUUTGGUUTGGGUUTGAGAGTATAG253ARGGGTGTUTGUTUUUAAGUTGGGUAUUUUTUUUUUAGGUTGTGGGAAURGUTGGGUUATTUTGAUUTRGAAUUAGAAATAGUUURGAUUUUUUTUTTTUTUUURGRGUUUUUAGURGGAURGUUUUURGGGAUUUUAGUUAAAUUAUAGXGTURGGUATAGGGUUTUTUUUTTATTGUAUAAURGUTAGGGGAGAUAGAGAGGATGGGGGTUURGGGAAUATGUTGGGGTRGUUAGAUTATGGGARGTAGGGGRGTAGUTUAUUTGTTGGAGAUAGGUURGUTUUTUAUTGGUTGAGTU254GAUTUAGUUAGTGAGGAGRGGGUUTGTUTUUAAUAGGTGAGUTARGUUUUTARGTUUUATAGTUTGGRGAUUUUAGUATGTTUURGGGAUUUUUATUUTUTUTGTUTUUUUTAGRGGTTGTGUAATAAGGGAGAGGUUUTATGURGGAXGUTGTGGTTTGGUTGGGGTUURGGGGGGRGGTURGGUTGGGGGRGRGGGGAGAAAGAGGGGGGTRGGGGUTATTTUTGGTTRGAGGTUAGAATGGUUUAGRGGTTUUUAUAGUUTGGGGGAGGGGTGUUUAGUTTGGGAGUAGAUAUURGT255GUAGTAAAUAGTUUTATTGTAUAAATATATAGRGRGGGUTGGGRGGGGGRGGTUAAUUURGGTTUUUTGGUARGGGGAUAGGGRGRGUTGGGUURGGUTUTGUAGRGAGURGGTGGGAGGGUUTAGUTGTGGUUUAGGRGGTGTTGAGUAXGGGURGGGGGRGTUATAGURGGGGAGGGURGGGUAGRGAGRGGGTGGGRGAGGGGRGAGTUATRGTUTGUUURGUURGGAGGGGAUUURGGRGGGTGAGGGARGTGGGTGGAGGGAGARGTGGGGAGUTUAGTRGGAGTAGATGATGAA256TTUATUATUTAUTURGAUTGAGUTUUUUARGTUTUUUTUUAUUUARGTUUUTUAUURGURGGGGTUUUUTURGGGRGGGGUAGARGATGAUTRGUUUUTRGUUUAUURGUTRGUTGUURGGUUUTUUURGGUTATGARGUUUURGGUUXGTGUTUAAUAURGUUTGGGUUAUAGUTAGGUUUTUUUAURGGUTRGUTGUAGAGURGGGUUUAGRGRGUUUTGTUUURGTGUUAGGGAAURGGGGTTGAURGUUUURGUUUAGUURGRGUTATATATTTGTAUAATAGGAUTGTTTAUTGU257AGTTATTTAATAUATGGUUUUAGTGGUAUTAAUUTGTUAUTAAGUUTUATGTTUTUUATUUATAAAATGGAGAUUAUAATUATAUUTGUTGUAAAATUUAAAATTUAGAGGTTTUTAUAGRGTGAURGAUAUTGTGUUURGGAGAGTTTXGGUUUTUTUUTGGUTUTGGUUUUUTGGAAUARGTGATGUUUAGUUUAAAUAGTGUUAUAUUUTGUTUTAUAATGUUTUAARGAGAGTUAUAAUUAAAGATTTTTGAGTUAGAGGAUAATAGAGGAGGTGGGAAUTGGGTAAAXGGAGAGT258UTUTUXGTTTAUUUAGTTUUUAUUTUUTUTATTGTUUTUTGAUTUAAAAATUTTTGGTTGTGAUTUTRGTTGAGGUATTGTAGAGUAGGGTGTGGUAUTGTTTGGGUTGGGUATUARGTGTTUUAGGGGGUUAGAGUUAGGAGAGGGUXGAAAUTUTURGGGGUAUAGTGTRGGTUARGUTGTAGAAAUUTUTGAATTTTGGATTTTGUAGUAGGTATGATTGTGGTUTUUATTTTATGGATGGAGAAUATGAGGUTTAGTGAUAGGTTAGTGUUAUTGGGGUUATGTATTAAATAAUTG259GAGTTTXGGUUUTUTUUTGGUTUTGGUUUUUTGGAAUARGTGATGUUUAGUUUAAAUAGTGUUAUAUUUTGUTUTAUAATGUUTUAARGAGAGTUAUAAUUAAAGATTTTTGAGTUAGAGGAUAATAGAGGAGGTGGGAAUTGGGTAAAXGGAGAGTUUATGGUUTTTGGAGGTGGGGUAUAGUURGGAGTGAATGAGGGUUUAGAGTTTUUAGAGAAURGAATATAGATUTGTGTGTGAAGUUTUUAGATATTUTAATGTTGAUAARGAAATUAAATTGAAAAAAAATAAAAATUAATA260ATTGATTTTTATTTTTTTTUAATTTGATTTRGTTGTUAAUATTAGAATATUTGGAGGUTTUAUAUAUAGATUTATATTRGGTTUTUTGGAAAUTUTGGGUUUTUATTUAUTURGGGUTGTGUUUUAUUTUUAAAGGUUATGGAUTUTUXGTTTAUUUAGTTUUUAUUTUUTUTATTGTUUTUTGAUTUAAAAATUTTTGGTTGTGAUTUTRGTTGAGGUATTGTAGAGUAGGGTGTGGUAUTGTTTGGGUTGGGUATUARGTGTTUUAGGGGGUUAGAGUUAGGAGAGGGUXGAAAUTUT261RGGGTGRGGAUURGUUAUUTGURGUAUUUTTUUUTTUUUAAUUUTGUUUTTTUUUUAUUUUUAUUUUAUTTUUUAUUUUUAAUUUURGUTRGGRGUUUUAUTUURGAUUUTGUUTGUURGGGUAUUTRGGGGRGTURGUTRGURGGUTTXGUUTUUAUTTGUUURGGUAGGRGRGRGTGGGUTRGGRGTUURGRGUTUUUTUUTRGAUTGTGRGGUTUURGRGUTGURGGGTTTUUTGTTUAAUAATATAAUUAGGGAGGUAURGGRGGAGAGRGURGGGUAGAAUTTUUTUURGGAUTG262UAGTURGGGAGGAAGTTUTGUURGGRGUTUTURGURGGTGUUTUUUTGGTTATATTGTTGAAUAGGAAAUURGGUAGRGRGGGAGURGUAUAGTRGAGGAGGGAGRGRGGGARGURGAGUUUARGRGRGUUTGURGGGGUAAGTGGAGGXGAAGURGGRGAGRGGARGUUURGAGGTGUURGGGUAGGUAGGGTRGGGAGTGGGGRGURGAGRGGGGGTTGGGGGTGGGAAGTGGGGTGGGGGTGGGGAAAGGGUAGGGTTGGGAAGGGAAGGGTGRGGUAGGTGGRGGGTURGUAUURG263GGUAAGGUAGTUTGGGRGURGTUTURGGTUTRGGGGUUTGRGGTRGGGGUAURGRGGTGURGRGTTTGAGURGGTUAGUTUUUTGRGGAAATTAUAGGGGRGUTRGGRGUTGRGGTRGRGUUUUURGGGGUAGRGUURGUTGGTTGGAGGXGTTTAAATTGAAAGUAGUTTTGGGGAGAGGGGGRGGARGRGGGURGURGAGUAAGGGGAGGGGGRGGUURGGUAUAGRGAUUUUATTGTUTGTGUURGURGAGGGGTGGAAUUTTGRGGTGAGUTRGGRGRGGRGUUUUUTUUURGAGU264GUTRGGGGAGGGGGRGURGRGURGAGUTUAURGUAAGGTTUUAUUUUTRGGRGGGUAUAGAUAATGGGGTRGUTGTGURGGGURGUUUUUTUUUUTTGUTRGGRGGUURGRGTURGUUUUUTUTUUUUAAAGUTGUTTTUAATTTAAAXGUUTUUAAUUAGRGGGRGUTGUUURGGGGGGRGRGAURGUAGRGURGAGRGUUUUTGTAATTTURGUAGGGAGUTGAURGGUTUAAARGRGGUAURGRGGTGUUURGAURGUAGGUUURGAGAURGGAGARGGRGUUUAGAUTGUUTTGUU265GGAGGGAGUUTGUAUTUTGGGUAGTGATGTGGAGTUAGAGATTTUUAAGTTUATGGTGUAAGTUTGTGGGAGAGUAGAAUTUAUTTTAUAAAATTGTTGAUAGURGGTGTTGTTAGAGARGGAAAGGGAUAAUUURGGUTUUTUTUUAGGXGTGGAGTUTGTGGGGATGTGUTTUUAGAAAATGUAGGGTTAAGUAGGAGUTGUAGAGTAGAATUAAATGAUAATGAUTUAUTGUTGTUAUTAAUAGGUTUTTTGTGGGGGUTGTAGGTGGGAGGRGATATGGURGGUAUUTTRGUAUAA266TTGTGRGAAGGTGURGGUUATATRGUUTUUUAUUTAUAGUUUUUAUAAAGAGUUTGTTAGTGAUAGUAGTGAGTUATTGTUATTTGATTUTAUTUTGUAGUTUUTGUTTAAUUUTGUATTTTUTGGAAGUAUATUUUUAUAGAUTUUAXGUUTGGAGAGGAGURGGGGTTGTUUUTTTURGTUTUTAAUAAUAURGGUTGTUAAUAATTTTGTAAAGTGAGTTUTGUTUTUUUAUAGAUTTGUAUUATGAAUTTGGAAATUTUTGAUTUUAUATUAUTGUUUAGAGTGUAGGUTUUUTUU267GTTUTGGTTRGGUAGAGTGGRGGUAATUTTGUUTUTUTUTUTAGAAUAUUTAAAGAAGUUAGTGAGTGAGUTGUTUATGUAUAURGGGGAGAUUTAUAGARGGATUUAGGAGGAGRGGGAGUTUATTGAUTGUAUAUTTUUAAUURGGXGTGATAGGAAAGTGAGGUUAUUTGTUUTAAGTGUURGGGGGUAGGGGGGTUUATGGAGGAGGGGGRGGGGGUAGGTGTUTGGAUAUAGGGATGUTGGTUTUAGGTGGUAUAGUTGGGGAGAAAAAAUUTATUUATTGUAAAAUATUATTAG268TAATGATGTTTTGUAATGGATAGGTTTTTTUTUUUUAGUTGTGUUAUUTGAGAUUAGUATUUUTGTGTUUAGAUAUUTGUUUURGUUUUUTUUTUUATGGAUUUUUUTGUUUURGGGUAUTTAGGAUAGGTGGUUTUAUTTTUUTATUAXGURGGGTTGGAAGTGTGUAGTUAATGAGUTUURGUTUUTUUTGGATURGTUTGTAGGTUTUUURGGTGTGUATGAGUAGUTUAUTUAUTGGUTTUTTTAGGTGTTUTAGAGAGAGAGGUAAGATTGURGUUAUTUTGURGAAUUAGAAUA269RGTGATUAGAGAUAGAAATUAGUTUUUUTUUTUUUTUAUTGAGUTTGTAGUUAUTTTAAGTATAAUUTGTGTUUTGTGUUAGTTUUAUUATAAATUAGUUUTGAGTTUTATURGGRGGUTTATTUTGUTGUUAAAAUUTTUATTAGTTGXGGGAATGGGUUAGGGAGAGAGUURGGAUTTTAUTURGGUTGTGGTGAUTUARGUUTTTGGGAAGGGUTGAGGTATTTGTUUTTGGATGTGGGGATGUTGTGGUUTUTGGTTGGGAAUAUAGUUTRGTTTTGTUTGUTGGUTUTGGUTTUU270GGAAGUUAGAGUUAGUAGAUAAAARGAGGUTGTGTTUUUAAUUAGAGGUUAUAGUATUUUUAUATUUAAGGAUAAATAUUTUAGUUUTTUUUAAAGGRGTGAGTUAUUAUAGURGGAGTAAAGTURGGGUTUTUTUUUTGGUUUATTUUXGUAAUTAATGAAGGTTTTGGUAGUAGAATAAGURGURGGATAGAAUTUAGGGUTGATTTATGGTGGAAUTGGUAUAGGAUAUAGGTTATAUTTAAAGTGGUTAUAAGUTUAGTGAGGGAGGAGGGGAGUTGATTTUTGTUTUTGATUARG271UAGTATGUATGTGTUUATTTAAGGUATUTGAGUUUTGGUUTTTGUTGTTUTTUUTTUUTTUTTTUTURGTRGGGTTGUTGAGUTUAAUATUUUAURGGGUTUUTGUTUUTTAGUTAGUAGTUAGTGUAGAGUTGUTGGGTUUTTUTGUUTXGUTTGGGUAGGUTTUTGTUAATGAGTUAUUAAGUAURGGGAAATAAGTGUAUAGGAAGGAGUAGGTGGUAAGAUUUTGTGGAGGTAGAGAUAGTTUUATTUAGTGAGTGAGUTGTGAUTGUAAATTTGGGAAGGTTUTGGGGGAAGUAA272TTGUTTUUUUUAGAAUUTTUUUAAATTTGUAGTUAUAGUTUAUTUAUTGAATGGAAUTGTUTUTAUUTUUAUAGGGTUTTGUUAUUTGUTUUTTUUTGTGUAUTTATTTUURGGTGUTTGGTGAUTUATTGAUAGAAGUUTGUUUAAGXGAGGUAGAAGGAUUUAGUAGUTUTGUAUTGAUTGUTAGUTAAGGAGUAGGAGUURGGTGGGATGTTGAGUTUAGUAAUURGARGGAGAAAGAAGGAAGGAAGAAUAGUAAAGGUUAGGGUTUAGATGUUTTAAATGGAUAUATGUATAUTG273RGGURGRGGGGGGRGUUTGGAGGAGGGAAGUUTUTURGGAGGAGAAGAGUTGGGRGGURGURGTAGGAGGAAGRGGAAAGATAAGGGGUUUTRGGUTRGGRGGGGURGURGGARGUUUAGGAGUUTUAATGGGGAUARGTRGGGTGGGGAXGGAGGUAGUTUUTGTURGGAUAGRGAAAUURGRGAGGUUUAGGAGAGRGGUAGUUAGRGRGGUAUAGUURGGGAGUTGRGGUUUARGURGGAGUUTARGGAUATGGGUTRGGAAGGGAUAAAAAURGGGURGGAGTUAGRGUTGGAGUU274GGUTUUAGRGUTGAUTURGGUURGGTTTTTGTUUUTTURGAGUUUATGTURGTAGGUTURGGRGTGGGURGUAGUTUURGGGUTGTGURGRGUTGGUTGURGUTUTUUTGGGUUTRGRGGGTTTRGUTGTURGGAUAGGAGUTGUUTUXGTUUUUAUURGARGTGTUUUUATTGAGGUTUUTGGGRGTURGGRGGUUURGURGAGURGAGGGUUUUTTATUTTTURGUTTUUTUUTARGGRGGURGUUUAGUTUTTUTUUTURGGAGAGGUTTUUUTUUTUUAGGRGUUUUURGRGGURG275GUATUAUAUATUUUTUUUTGTUTUUUTGUTGUUAAUUAGTTUUAUUAUTGTGUAUUTUTGUUUUAATTUUAUUTUUUARGUUTGUTGUTGUAUUTTGGAUTTGTTTTUUTGAAATTGUATGUUATUUAUTUTUUUTTUTAUTTUTGUTGXGTUUUTUTTGUUUTATUAGGAUUTGTGGAUTUAGGAUTUURGGGUTTTUTUUUUUATUTUTUTTUUURGTTGGGUUTUAUTAUUATTTUAGUUAUTTTUUTGGUAGUTTUAUTUUTGUUUUAAGAUUUUAGUUTUUAUUUTUUTGGTTUT276AGAAUUAGGAGGGTGGAGGUTGGGGTUTTGGGGUAGGAGTGAAGUTGUUAGGAAAGTGGUTGAAATGGTAGTGAGGUUUAARGGGGAAGAGAGATGGGGGAGAAAGUURGGGAGTUUTGAGTUUAUAGGTUUTGATAGGGUAAGAGGGAXGUAGUAGAAGTAGAAGGGAGAGTGGATGGUATGUAATTTUAGGAAAAUAAGTUUAAGGTGUAGUAGUAGGRGTGGGAGGTGGAATTGGGGUAGAGGTGUAUAGTGGTGGAAUTGGTTGGUAGUAGGGAGAUAGGGAGGGATGTGTGATGU277GGTGGRGATGUTUTAGUUAUUTGUTTUTUTGTUUTUTTTUAUAUAAATGTATUUTGUTTUTTTUUAGATGTURGGUTTAATGGGAUTGGATTTATUTTUAAAAGTUUTGGTTTGUUTUTGATTGAAAAUUAGTGTGUTUUUUATGGTTAXGGARGGUTGTGUAGGTTTTTGTTTTGTTGAAGGGAATTGGUTUAUTUTGAGTUAGURGTGUAUURGGGUTGUTGATGTAGTUTUAGTGTGATGGTTAAAUTTTAAGTGTUAATTTGAUTGGGUTAAGGAATGUUAGAUATTATTTURGGG278UURGGAAATAATGTUTGGUATTUUTTAGUUUAGTUAAATTGAUAUTTAAAGTTTAAUUATUAUAUTGAGAUTAUATUAGUAGUURGGGTGUARGGUTGAUTUAGAGTGAGUUAATTUUUTTUAAUAAAAUAAAAAUUTGUAUAGURGTUXGTAAUUATGGGGAGUAUAUTGGTTTTUAATUAGAGGUAAAUUAGGAUTTTTGAAGATAAATUUAGTUUUATTAAGURGGAUATUTGGAAAGAAGUAGGATAUATTTGTGTGAAAGAGGAUAGAGAAGUAGGTGGUTAGAGUATRGUUAUU279GGTTTTGGGTGTGGAUATUUTGGAGGGUTGTTTTAGTGUUUAUAUUAATGUUUTAGTTAAAGAAUUAUUUTGTUUUUTTAGUUTTUTGUAGGAUAGGTGGGAAAGGGURGGGTGTUTGGTUUTGUTGUUAGGGGAUAGTGUAGGTGTGAUXGTURGGGUAGAGATGAGTUAUUUTUUAUAUTGTUTTGUTGUURGTUTUUARGUUTAGTTTTAGUTRGTGTGGTUAAGAAGGGGRGATTUUTUAUUTAGAAUAUATGGGTUAUAAATGUTAUUTTTGAAAATGGAAAUAAAAATAAUUUA280TGGGTTATTTTTGTTTUUATTTTUAAAGGTAGUATTTGTGAUUUATGTGTTUTAGGTGAGGAATRGUUUUTTUTTGAUUAUARGAGUTAAAAUTAGGRGTGGAGARGGGUAGUAAGAUAGTGTGGAGGGTGAUTUATUTUTGUURGGAXGGTUAUAUUTGUAUTGTUUUUTGGUAGUAGGAUUAGAUAUURGGUUUTTTUUUAUUTGTUUTGUAGAAGGUTAAGGGGAUAGGGTGGTTUTTTAAUTAGGGUATTGGTGTGGGUAUTAAAAUAGUUUTUUAGGATGTUUAUAUUUAAAAUU281UAGAAUUTGAGRGATGAAGTGARGGGATTTAGTUAGGUUTATGAAGAGTUAATGGUAUTTGUUTUUUATAATUUTTUUAGTUUUATTGGUUAAUURGTUTGTUUUTRGRGTGATUTTTTTGGATUTGAAGTGGTGTTTUAGGAUURGGAGXGTGGUUTGUAUTGUUTTGTTUTGTTTGTTTGTGUAURGGATTUATRGTGAUTUATUUTGAGTUATUUAGGUAGTATGGAAGAAUTTTGGAGTTATTTTAAAUUUTTTGGUTUAGAAUUUUATTTUTTUTAGAATTAAUATGUAAGATAA282TTATUTTGUATGTTAATTUTAGAAGAAATGGGGTTUTGAGUUAAAGGGTTTAAAATAAUTUUAAAGTTUTTUUATAUTGUUTGGATGAUTUAGGATGAGTUARGATGAATURGGTGUAUAAAUAAAUAGAAUAAGGUAGTGUAGGUUAXGUTURGGGTUUTGAAAUAUUAUTTUAGATUUAAAAAGATUARGRGAGGGAUAGARGGGTTGGUUAATGGGAUTGGAAGGATTATGGGAGGUAAGTGUUATTGAUTUTTUATAGGUUTGAUTAAATUURGTUAUTTUATRGUTUAGGTTUTG283GTUUUTTGGUAUUAGGAUATUAUUUTUUUAUUTUTUUUAGAUUUTTUTUUTTGAUUTUTTTAGAGUAGUUATUUTTGGAGTTGUTUAARGUUUTUTTUTUTTUTUUUTUTGAAUUAUAGUTTGGUTUATUTAUTTURGGGTTAGUTUAAXGUUUTUTTUTTTTUTUUUTUTGAAUUAUAGUTTGGUTUATUTAUTTURGGGTTAGUTUAARGUAUTUTTUTUTTUTUUUTUTGAAUUARGGUTTGGUTUATUTAUTTUTGGGTTAATTTAGGUTTTUTUUAUAGATAGTUTGAAAAGGGA284TUUUTTTTUAGAUTATUTGTGGAGAAAGUUTAAATTAAUUUAGAAGTAGATGAGUUAAGURGTGGTTUAGAGGGAGAAGAGAAGAGTGRGTTGAGUTAAUURGGAAGTAGATGAGUUAAGUTGTGGTTUAGAGGGAGAAAAGAAGAGGGXGTTGAGUTAAUURGGAAGTAGATGAGUUAAGUTGTGGTTUAGAGGGAGAAGAGAAGAGGGRGTTGAGUAAUTUUAAGGATGGUTGUTUTAAAGAGGTUAAGGAGAAGGGTUTGGGAGAGGTGGGAGGGTGATGTUUTGGTGUUAAGGGAU285UTGAGTUAAUAAGGUTGAUAAGGUTGTGTTUTGGATGUAGGUURGGUAGATGTTTGAGGGGGAGGTGGUUAGUUTGGAGGUUUTUAGGAGUARGGGUUTGGTGRGGGTGURGAGGUUUATGAAGGTUATRGAUUTGURGGGAGGTGGGGUXGUUTTTGTGATGGAGUATTTGAAGATGAAGAGUTTGAGUAGGTGAGTGTGTGTGAGAUUUATATGRGUAUATGTGTAUAGGUAGAGAGAGAUTUAGAGAUAAAUAGAGAGAGAUAGAGAAAGGGATAGAGATGGGGAGGGAGAUAGAAA286TTTUTGTUTUUUTUUUUATUTUTATUUUTTTUTUTGTUTUTUTUTGTTTGTUTUTGAGTUTUTUTUTGUUTGTAUAUATGTGRGUATATGGGTUTUAUAUAUAUTUAUUTGUTUAAGUTUTTUATUTTUAAATGUTUUATUAUAAAGGXGGUUUUAUUTUURGGUAGGTRGATGAUUTTUATGGGUUTRGGUAUURGUAUUAGGUURGTGUTUUTGAGGGUUTUUAGGUTGGUUAUUTUUUUUTUAAAUATUTGURGGGUUTGUATUUAGAAUAUAGUUTTGTUAGUUTTGTTGAUTUAG287TTRGTGUAUTUTGRGGURGRGGRGGUAGUAGURGRGGRGGRGGUUAGUTUUURGGTUTARGTGUUUAUUAUURGRGTGGGTTUUATGUTGUURGGUUTAURGTAUUAUUTGUAGGGGTRGGGUAGTGGGUUAGUUAAUUARGRGGGRGGXGRGGGRGRGUAUUURGGUTGGUUTUAGGUUTRGGURGAUAGUUUTUUATARGGUAGRGGAGGRGGRGRGGUTGGRGGRGGGGURGRGGGGUUTGGRGGRGUTGGUTUAGURGRGGRGUARGTUTRGGRGRGUTTUUUUTAUTUTUUUAGU288GUTGGGAGAGTAGGGGAAGRGRGURGAGARGTGRGURGRGGUTGAGUUAGRGURGUUAGGUUURGRGGUUURGURGUUAGURGRGURGUUTURGUTGURGTATGGAGGGUTGTRGGURGAGGUUTGAGGUUAGURGGGGTGRGRGUURGXGURGUURGRGTGGTTGGUTGGUUUAUTGUURGAUUUUTGUAGGTGGTARGGTAGGURGGGUAGUATGGAAUUUARGRGGGTGGTGGGUARGTAGAURGGGGAGUTGGURGURGURGRGGUTGUTGURGURGRGGURGUAGAGTGUARGAA289TUTTTGTGTGAGTUATGTUTTATATUUAAUAAGTAUTUAAAAAAAGATTTTTTTTTTTTTTTTTTAAGATGGAGTGTRGUTUTGTUAUUUAGGUTGGAGTGUAGTGGUATGATUTTGGUTUAUTGUAAUUTUTGUUTUURGGGTTUAAGXGATTUTTUTGUUTUAGGUTUUTGAGTAGUTGGAATTAUAGGUATGUUUUAUUAUAUURGGUTAATTTTTATATGTAATAGAAAUAAGGTTTUAUUATGTTGGUUAGAUAGGTUTTGAAUTUUTGAUUTUAGGTGATUUAUUUAUUTRGGU290GURGAGGTGGGTGGATUAUUTGAGGTUAGGAGTTUAAGAUUTGTUTGGUUAAUATGGTGAAAUUTTGTTTUTATTAUATATAAAAATTAGURGGGTGTGGTGGGGUATGUUTGTAATTUUAGUTAUTUAGGAGUUTGAGGUAGAAGAATXGUTTGAAUURGGGAGGUAGAGGTTGUAGTGAGUUAAGATUATGUUAUTGUAUTUUAGUUTGGGTGAUAGAGRGAUAUTUUATUTTAAAAAAAAAAAAAAAAAATUTTTTTTTGAGTAUTTGTTGGATATAAGAUATGAUTUAUAUAAAGA291AUUAUUUUUTGAUUUUTUATGAUTUAUUUAGUTUUTAAGTGUUUUTGGGUAUUUAGTTUTTTGTGGUATGGGURGGTGUAAGTTTUTATATGAGAGUUAGAGAGAUAGGGAGGGAGGUURGGGUTUUTGGUUTTTTGGGAAAAGATGUUXGTUTUAGAUUAGUAAAAGGAGGUAGUTGUTTTAGGAGUURGGGAAAATGUUATUAUTGATAGTATTATTATTATTTTUUUATTTTUUUTTTGTGTTTTTAAAATGAAAAGTTUAGATUUATGGGGTAGGGTAGAGTGGGUUTGGAGGGAG292TUUUTUUAGGUUUAUTUTAUUUTAUUUUATGGATUTGAAUTTTTUATTTTAAAAAUAUAAAGGGAAAATGGGAAAATAATAATAATAUTATUAGTGATGGUATTTTUURGGGUTUUTAAAGUAGUTGUUTUUTTTTGUTGGTUTGAGAXGGGUATUTTTTUUUAAAAGGUUAGGAGUURGGGUUTUUUTUUUTGTUTUTUTGGUTUTUATATAGAAAUTTGUAURGGUUUATGUUAUAAAGAAUTGGGTGUUUAGGGGUAUTTAGGAGUTGGGTGAGTUATGAGGGGTUAGGGGGTGGTT293GUAGUARGUAGUUUUUAGGGGUUUTAAUTUAUUUUUTUTTUUUTUAUAGGGUTTUUUTGURGTUUAGTGTTGGGTGAGAAAGGTGGAGGGGAUATGTAGUUURGGATGGAGGTGUAGUAUUAARGAGAGAGUTURGGUUTGTGGGAGGGAXGUTUAGGUTTAGGTUAAAGUUAGGAGUTURGGGAAAUUTGGGTTUAGURGUUARGUUUUARGGAGGGGAUAUAUUUTTUUUTGUUTGATGGUAGGGUUUATGGTAGAUAAAAUUUATGAUUTUAUUTUTUUTGGUTUUAGGGUTUAGUU294GGUTGAGUUUTGGAGUUAGGAGAGGTGAGGTUATGGGTTTTGTUTAUUATGGGUUUTGUUATUAGGUAGGGAAGGGTGTGTUUUUTURGTGGGGRGTGGRGGUTGAAUUUAGGTTTUURGGAGUTUUTGGUTTTGAUUTAAGUUTGAGXGTUUUTUUUAUAGGURGGAGUTUTUTRGTTGGTGUTGUAUUTUUATURGGGGUTAUATGTUUUUTUUAUUTTTUTUAUUUAAUAUTGGARGGUAGGGAAGUUUTGTGAGGGAAGAGGGGGTGAGTTAGGGUUUUTGGGGGUTGRGTGUTGU295ATTTUTTTUTAUUTGTUATTGAAGTGAATUATUAGTATAAGTAGRGAGUTGGGRGUATTUUTTUTUAGTTGTGTTAAAAUTTGUTGGTATTUUUURGGTATUAGUAGAGGTGTGTARGGGUAUTGUTTTAAAAUTGGGAAGGAGGAAGAXGAGGUUAGGGAGURGGAGGGTUAUUAAGGTAGATTTUUAGUAGRGUTAGTUUAGUTGAAUAUTTTUUAGUUTTGTTTTTUAGUAGUTTTGAGGAAAAGTATAGGTAAGAAUAAAGAUAUUAUTGTATGTTTGUTATATGAATGUATAAUA296GTTATGUATTUATATAGUAAAUATAUAGTGGTGTUTTTGTTUTTAUUTATAUTTTTUUTUAAAGUTGUTGAAAAAUAAGGUTGGAAAGTGTTUAGUTGGAUTAGRGUTGUTGGAAATUTAUUTTGGTGAUUUTURGGUTUUUTGGUUTXGTUTTUUTUUTTUUUAGTTTTAAAGUAGTGUURGTAUAUAUUTUTGUTGATAURGGGGGAATAUUAGUAAGTTTTAAUAUAAUTGAGAAGGAATGRGUUUAGUTRGUTAUTTATAUTGATGATTUAUTTUAATGAUAGGTAGAAAGAAATG297ATTGGTUTGGTUUTUTTTUTAAUAUUTUUUAUURGGGATGUAGUUAAGAGTGGUTGUAGUUTAATTTTUTAUATGTAAAUAATGAUUTUAGTGATGUUUARGGGGUUUUTUTUTGGUUTTUTUUUUUTGGGAAAAGAUTGAGTTUTRGAXGGGUATUUUUTUUUUUTURGGAAUUAAGGGUTUTGGGATGTTGAUAGUUUURGUUAUUTUTGAGAAGGGUAGGURGTGGAAAAUUATUTUUTUUUTTUUTTUUUUUTUTGUUTTTUUTAGUTGGGGUUTUTGUAUAATGUAGUTGGGUUA298TGGUUUAGUTGUATTGTGUAGAGGUUUUAGUTAGGAAAGGUAGAGGGGGAAGGAAGGGAGGAGATGGTTTTUUARGGUUTGUUUTTUTUAGAGGTGGRGGGGGUTGTUAAUATUUUAGAGUUUTTGGTTURGGAGGGGGAGGGGATGUUXGTRGAGAAUTUAGTUTTTTUUUAGGGGGAGAAGGUUAGAGAGGGGUUURGTGGGUATUAUTGAGGTUATTGTTTAUATGTAGAAAATTAGGUTGUAGUUAUTUTTGGUTGUATUURGGGTGGGAGGTGTTAGAAAGAGGAUUAGAUUAAT299TTGUUUTUATUTUUAGGUTTTGGAGGAGGGTAGGTGUUTGGUUAGUAGAGTGGUUAUTGUTUAUTGGUUUAGAGGAAGUAAGGUUAUUAGUUTGATUUUAUTTUTUUUTURGGUUUATUTTUAUTUUUUTUTUUTUAAUUAUAAGUUUXGUUAAAATAGAGAUUUURGGUTTTGUTUUUUTGUTGUAGGAAGGGAGAGUUAURGUUAGAUAUTGUUTGUUTGGTUUTUUTGTTUTGATUTUAUURGGTGUTTGGAATUAAAGAGGAUUTGGUTTUUUTUTRGGGATARGTGATTTTUTTT300AAGAAAATUARGTATUURGAGAGGGAAGUUAGGTUUTUTTTGATTUUAAGUAURGGGTGAGATUAGAAUAGGAGGAUUAGGUAGGUAGTGTUTGGRGGTGGUTUTUUUTTUUTGUAGUAGGGGAGUAAAGURGGGGGTUTUTATTTTGGXGGGGUTTGTGGTTGAGGAGAGGGGAGTGAAGATGGGURGGAGGGAGAAGTGGGATUAGGUTGGTGGUUTTGUTTUUTUTGGGUUAGTGAGUAGTGGUUAUTUTGUTGGUUAGGUAUUTAUUUTUUTUUAAAGUUTGGAGATGAGGGUAAG301GUUUAGATUAGGUAGRGGGGTRGUUUTUTUUAGGAUTUTUAAGGUAGUTAAGGUTGGAGGRGURGGRGAGUUTGGAGAGGGAGGAGTTUAUTAAATTGTGTTGGATGGAAGGRGTRGAGGAURGGAGGAATTAATURGATGTGGGGAAGGXGGARGGGGUTARGAGGAAAAAAGAGGGGGUAATGTAUAUTUAGUUTTTTUATUAUTRGGRGGGGAGATGGATGGTTTTURGGAURGGGRGTUUUAGRGUUURGGTTAGUTATAGGGAGARGTUAGAGRGUTUTGGTURGRGATAGAAGA302TUTTUTATRGRGGAUUAGAGRGUTUTGARGTUTUUUTATAGUTAAURGGGGRGUTGGGARGUURGGTURGGAAAAUUATUUATUTUUURGURGAGTGATGAAAAGGUTGAGTGTAUATTGUUUUUTUTTTTTTUUTRGTAGUUURGTUXGUUTTUUUUAUATRGGATTAATTUUTURGGTUUTRGARGUUTTUUATUUAAUAUAATTTAGTGAAUTUUTUUUTUTUUAGGUTRGURGGRGUUTUUAGUUTTAGUTGUUTTGAGAGTUUTGGAGAGGGRGAUUURGUTGUUTGATUTGGGU303ATTTGGUTTGATUTTATTTTTAATATTTTTTAUAUTTTUTUTUTAAAGAAAAAAAAGGRGAGTGAATATRGTGATGGGTGUAGTTATGUTGAATAATTGGATGGGAGGARGTGUUAGGRGATUTUUAGUUUUTGGGAGURGGARGUUUAXGUUTUUUTUTGUUTRGTTUTUAUAGAUAUATTTGTGGGGTGATTAAUTUAGGAATTUATGUTGUTUAAAGTAAUTAUAGTGGTGAGTGTTTTGAURGGTTTGATGTAGAAATUAAGGAAAAUAUUAGAAAAATUAGGGGRGGAGGUUUAA304TTGGGUUTURGUUUUTGATTTTTUTGGTGTTTTUUTTGATTTUTAUATUAAAURGGTUAAAAUAUTUAUUAUTGTAGTTAUTTTGAGUAGUATGAATTUUTGAGTTAATUAUUUUAUAAATGTGTUTGTGAGAARGAGGUAGAGGGAGGXGTGGGRGTURGGUTUUUAGGGGUTGGAGATRGUUTGGUARGTUUTUUUATUUAATTATTUAGUATAAUTGUAUUUATUARGATATTUAUTRGUUTTTTTTTTUTTTAGAGAGAAAGTGTAAAAAATATTAAAAATAAGATUAAGUUAAAT305TGAUTTTTTUATTTUTUTUAAGATGATUATTAGGAGTGGTTTUAAUAAAAUTGAAUAUAGAATTTTGAGGGUUUUAATUATGAUTUAAUUAGAGUUUTUUUTGAATTUTTUATGAGTUAGUURGGUUUTUUUUAUTGAUTTUAUUUTAGXGGGUAUUTGTUTTTUTTUTTUTTTTATUAUTTTTTGUTTUTUTTTTGGTTTUUAGUTUTGAUTGAATTUAGAUUUAAUAUUTTUUAATTUTTUURGGUUUUUTUAGGGAAAUUUAGAGGUAAATTTGAGTGUAGGGAGRGGGGGUTTRGU306GRGAAGUUUURGUTUUUTGUAUTUAAATTTGUUTUTGGGTTTUUUTGAGGGGGURGGGAAGAATTGGAAGGTGTTGGGTUTGAATTUAGTUAGAGUTGGAAAUUAAAAGAGAAGUAAAAAGTGATAAAAGAAGAAGAAAGAUAGGTGUUXGUTAGGGTGAAGTUAGTGGGGAGGGURGGGUTGAUTUATGAAGAATTUAGGGAGGGUTUTGGTTGAGTUATGATTGGGGUUUTUAAAATTUTGTGTTUAGTTTTGTTGAAAUUAUTUUTAATGATUATUTTGAGAGAAATGAAAAAGTUA307GGTGTUAGGAGTGGUUUAGGAGAGUAUUURGTTUUURGGUURGUAGGTGGTGTTTGUTGGUTUUAGUAGGGUUAGGAGGUUAUUTGUAGUUTGGTGUTUUAGAUTGATGTUAUURGGGURGAGTGUTGTGUUTURGGUAAUATTGAUAUXGUUTGGTUUAAUUTUAUUUAUURGGGGAAUAAGATUAAUUTUUTRGGUTTUTTGGGUUTTGTUUAUTGUUTTUUUTGUAAAGGTGAGAUUTUAGGUUAGAAGUAGGGUAGARGTUTUAGUTUAGGAUUAGUUAUAAAUAGTUATGGTGGT308AUUAUUATGAUTGTTTGTGGUTGGTUUTGAGUTGAGARGTUTGUUUTGUTTUTGGUUTGAGGTUTUAUUTTTGUAGGGAAGGUAGTGGAUAAGGUUUAAGAAGURGAGGAGGTTGATUTTGTTUUURGGGTGGGTGAGGTTGGAUUAGGXGGTGTUAATGTTGURGGAGGUAUAGUAUTRGGUURGGGTGAUATUAGTUTGGAGUAUUAGGUTGUAGGTGGUUTUUTGGUUUTGUTGGAGUUAGUAAAUAUUAUUTGRGGGURGGGGAARGGGGTGUTUTUUTGGGUUAUTUUTGAUAUU309GUAGUUUTUTTUAUUTGUUTGGTGAUTUAUTAUAAGUUUTGGGGGAAGGAATGGUAGTGGUUUTUTTUAUUTTTAUTGUUTUTGRGGUUAUAATGGGUAGTTGAUATAAUUAUUTGUAGGUUURGGGAGUUATXGGGGUUTUTTGAUAXGTGUTUATTAGTGGUTTUTGAGGAGRGUUTGUUUUAUUTGUUUUAXGTGUUUUUAXGTUTGGUUAUTUUAGGGTUUATTAGRGUTAATRGGUAAATGUUTGTGUTUTUATUTAURGGGAAAAUATUTUUUTTUTUUAGAGRGGAGGUUAGU310UTGGUUTURGUTUTGGAGAAGGGAGATGTTTTUURGGTAGATGAGAGUAUAGGUATTTGURGATTAGRGUTAATGGAUUUTGGAGTGGUUAGAXGTGGGGGUAXGTGGGGUAGGTGGGGUAGGRGUTUUTUAGAAGUUAUTAATGAGUAXGTGTUAAGAGGUUUXGATGGUTUURGGGGUUTGUAGGTGGTTATGTUAAUTGUUUATTGTGGURGUAGAGGUAGTAAAGGTGAAGAGGGUUAUTGUUATTUUTTUUUUUAGGGUTTGTAGTGAGTUAUUAGGUAGGTGAAGAGGGUTGUT311GTGGUUUTUTTUAUUTTTAUTGUUTUTGRGGUUAUAATGGGUAGTTGAUATAAUUAUUTGUAGGUUURGGGAGUUATRGGGGUUTUTTGAUAXGTGUTUATTAGTGGUTTUTGAGGAGRGUUTGUUUUAUUTGUUUUAXGTGUUUUUAXGTUTGGUUAUTUUAGGGTUUATTAGRGUTAATRGGUAAATGUUTGTGUTUTUATUTAURGGGAAAAUATUTUUUTTUTUUAGAGRGGAGGUUAGUUTAAAAAUUAGGUURGUAGUUTURGAGGUTUTGAAAAUUAAGRGGUTGTTUTGGTU312AUUAGAAUAGURGUTTGGTTTTUAGAGUUTRGGAGGUTGRGGGUUTGGTTTTTAGGUTGGUUTURGUTUTGGAGAAGGGAGATGTTTTUURGGTAGATGAGAGUAUAGGUATTTGURGATTAGRGUTAATGGAUUUTGGAGTGGUUAGAXGTGGGGGUAXGTGGGGUAGGTGGGGUAGGRGUTUUTUAGAAGUUAUTAATGAGUAXGTGTUAAGAGGUUURGATGGUTUURGGGGUUTGUAGGTGGTTATGTUAAUTGUUUATTGTGGURGUAGAGGUAGTAAAGGTGAAGAGGGUUAUT313ATGGGUUUTGGGGURGURGUUTUAGTGTUTTUTGGTGUTGUAGURGGGUAGGGURGAAUUUTGGRGUAUAGUTTUUTGUTGAGTUTUUUTUTUTAAGGUTGTUTGTGGGRGGUTUTGURGGUUUUTUUTGUAUUTGUUUAGGUUUTGGGXGGAGGUTUUTUUTUURGGGGGGGUTGTGGUUTUAGUAUAGAUUAGGGGAUAGAAGGTGGUTUTTUTTGGUUTTGGUTGGGTGTGAAUUAAAGAUTTUUTGTAAGAAATUUUUUTUTUUUTUTUUUTUUTTRGUTUUUTUATUTUTUTUUU314GGGAGAGAGATGAGGGAGRGAAGGAGGGAGAGGGAGAGGGGGATTTUTTAUAGGAAGTUTTTGGTTUAUAUUUAGUUAAGGUUAAGAAGAGUUAUUTTUTGTUUUUTGGTUTGTGUTGAGGUUAUAGUUUUUURGGGAGGAGGAGUUTUXGUUUAGGGUUTGGGUAGGTGUAGGAGGGGURGGUAGAGURGUUUAUAGAUAGUUTTAGAGAGGGAGAUTUAGUAGGAAGUTGTGRGUUAGGGTTRGGUUUTGUURGGUTGUAGUAUUAGAAGAUAUTGAGGRGGRGGUUUUAGGGUUUAT315UAUTGGAUUATUUAUAUAAUTTTTGAGGATUAGTGGAAATGAAAAUARGGTGUUURGGUAUAAAAUATATTTUATAGUTTGGGTTAGGUAAUAGUAAAGUATUARGUTGAGRGURGGGAUUTTUTGAGTGUAGGXGGTGGGXGAAGUUURGAGTUAUAUAUAUUUARGAXGURGGUUUTGUTUUUAUAGRGGUUUTUTGGGGTAGRGAUTGGTATTAUUTGUATTTUARGAGGGAGGAAAUTGAGGUARGAAUTGTTUAGAAGUTGUUUTGAGGTUAUUAAGTGAGUTAGGAAGAGGRGT316RGUUTUTTUUTAGUTUAUTTGGTGAUUTUAGGGUAGUTTUTGAAUAGTTRGTGUUTUAGTTTUUTUUUTRGTGAAATGUAGGTAATAUUAGTRGUTAUUUUAGAGGGURGUTGTGGGAGUAGGGURGGXGTRGTGGGTGTGTGTGAUTRGGGGUTTXGUUUAUXGUUTGUAUTUAGAAGGTUURGGRGUTUAGRGTGATGUTTTGUTGTTGUUTAAUUUAAGUTATGAAATATGTTTTGTGURGGGGUAURGTGTTTTUATTTUUAUTGATUUTUAAAAGTTGTGTGGATGGTUUAGTGT317UTUUAGTGTGUUTUAGTTGGTTTATUTGTAAAAATGGGGUUAGGUUARGAUTGGTGTTUUUTTTAUAGAGAAGUAUTUUAGGUAGGGGTGGGTGGGGGTGGAAUTRGTTUTUAATGGUUUURGGGAUAGUUUTGUAGUUAURGGTGAUTXGGGTTXGTUTGRGGATUTTTUURGGUUTUUAUTUUATTUAGGGAUAGUUUTGUAATGGGGUTUUUTUUUAAAAAAARGUATGGUUTTUUTGTUUUUUAAAAUUAGUTTAARGGUAGUUATTUUUTUUUTUUTURGGGGGUTGAAAAAUUA318GGTTTTTUAGUUUURGGAGGAGGGAGGGAATGGUTGURGTTAAGUTGGTTTTGGGGGAUAGGAAGGUUATGRGTTTTTTTGGGAGGGAGUUUUATTGUAGGGUTGTUUUTGAATGGAGTGGAGGURGGGAAAGATURGUAGAXGAAUUXGAGTUAURGGTGGUTGUAGGGUTGTUURGGGGGUUATTGAGAARGAGTTUUAUUUUUAUUUAUUUUTGUUTGGAGTGUTTUTUTGTAAAGGGAAUAUUAGTRGTGGUUTGGUUUUATTTTTAUAGATAAAUUAAUTGAGGUAUAUTGGAGG319UAUTUARGGGUTAGUTURGTUAGGTGTTGARGGATGTUAUTUAGGTGTGAGUTUTGUAUUTGAGUTUUUUUUTGUAUAUAGGUAGUUAUAAUUAGTUAGTGUAGAGGTGAGUUTGTGGUUAGTGAGGAGURGGTGAGTUAAUUTUUTUUXGUUTARGGGUUUTGAGARGURGGUTURGTGAGUTTGRGGGGTRGAGGGRGUUTATATTAAGUUAAGGUTGAGGUAGTGAUAUAUUUTUTTATGGGUUTGUTUTRGUTUUUTGUTTUATTGTUUTGGTUTUTUUUTUTRGTATGGAGGATUA320TGATUUTUUATARGAGAGGGAGAGAUUAGGAUAATGAAGUAGGGAGRGAGAGUAGGUUUATAAGAGGGTGTGTUAUTGUUTUAGUUTTGGUTTAATATAGGRGUUUTRGAUUURGUAAGUTUARGGAGURGGRGTUTUAGGGUURGTAGGXGGGAGGAGGTTGAUTUAURGGUTUUTUAUTGGUUAUAGGUTUAUUTUTGUAUTGAUTGGTTGTGGUTGUUTGTGTGUAGGGGGGAGUTUAGGTGUAGAGUTUAUAUUTGAGTGAUATURGTUAAUAUUTGARGGAGUTAGUURGTGAGTG321UUAGGUTGUUTGGGTTTTGGTUTUUAUUATGUTAGUTTGGTGTURGAUUTGTGTTGAGAUUUTUUUTGUUTUTGGUURGGGTGTUUUATUUAAGUAATGGAUAGGTTGGAAUAGGXGTTXGTAGGGAAXGGGUTGAAXGUURGRGGUTUUXGXGATGTUTXGXGATAUTAUUTUUUTXGUUUUXGUTUAUTTAAGGAURGGAAGTAGUAAAGUURGURGTRGRGUUUUURGUUURGRGTUTUUUTGGTAAUUAGUUTUTUUUUTTUUUTRGUUUATAAGGAGUAAGRGGUAUAAATRGGG322UURGATTTGTGURGUTTGUTUUTTATGGGRGAGGGAAGGGGAGAGGUTGGTTAUUAGGGAGARGRGGGGRGGGGGGRGRGARGGRGGGUTTTGUTAUTTURGGTUUTTAAGTGAGXGGGGGXGAGGGAGGTAGTATXGXGAGAUATXGXGGGAGURGRGGGXGTTUAGUUXGTTUUUTAXGAAXGUUTGTTUUAAUUTGTUUATTGUTTGGATGGGAUAUURGGGUUAGAGGUAGGGAGGGTUTUAAUAUAGGTRGGAUAUUAAGUTAGUATGGTGGAGAUUAAAAUUUAGGUAGUUTGG323UAATGGUUTUTTTUTTUAGUUTRGGTGGGRGTGGUTGGGGGAAUUUUAGGGRGGGRGGGGGGUAGGGGGTGGTGUTGAGTUAUUUAGUUTGGUUAGGTUUUTGUUTGUUAGUUUUUTGUUUUUAURGUTAUAGUURGUUURGGATUTAXGAGGUUUAGUUAGUUAUUTUTGGAUTUUTGAGAUXGAATTGUAAAUTGUURGGGUUTGGUUTTGAAUTUUTGUTGTTTAGGGAUUAAGTUUTGTGGUTUUUAGGGGGGUAUAGTGATUTUTUAAGUTGAGUTGGUUTUAGGGUUTUTGUAU324TGUAGAGGUUUTGAGGUUAGUTUAGUTTGAGAGATUAUTGTGUUUUUUTGGGAGUUAUAGGAUTTGGTUUUTAAAUAGUAGGAGTTUAAGGUUAGGUURGGGUAGTTTGUAATTXGGTUTUAGGAGTUUAGAGGTGGUTGGUTGGGUUTXGTAGATURGGGGRGGGUTGTAGRGGTGGGGGUAGGGGGUTGGUAGGUAGGGAUUTGGUUAGGUTGGGTGAUTUAGUAUUAUUUUUTGUUUUURGUURGUUUTGGGGTTUUUUUAGUUARGUUUAURGAGGUTGAAGAAAGAGGUUATTGT325AUUUTGTGUAGGGUUTGUATUURGGAAGGUUTUUAUUAGUURGAAUUTGGUURGTURGUUUTAGATGGGGUAATRGGRGTTTUTUURGGGAUAGUUTUUTUUUTGGUUTUUTGGUUUTRGTUTGUATTGAGAGGUTTGGUUTUTGGTUXGUATGUTGUUUTTUURGTGUTGTGGUUTTGUAGUURGGUUTUTUUUUTGUTGTUUUUUTTGGUTUTGGUUTGGUUUUTGGGUUUUTGAGTUAUUUUTGAGGTGAUTUAGUAGTUUTTGGAAARGUATGURGAGGARGUAUUUTGUUTGGUU326GUUAGGUAGGGTGRGTUUTRGGUATGRGTTTUUAAGGAUTGUTGAGTUAUUTUAGGGGTGAUTUAGGGGUUUAGGGGUUAGGUUAGAGUUAAGGGGGAUAGUAGGGGAGAGGURGGGUTGUAAGGUUAUAGUARGGGAAGGGUAGUATGXGGAUUAGAGGUUAAGUUTUTUAATGUAGARGAGGGUUAGGAGGUUAGGGAGGAGGUTGTUURGGGAGAAARGURGATTGUUUUATUTAGGGRGGARGGGUUAGGTTRGGGUTGGTGGAGGUUTTURGGGATGUAGGUUUTGUAUAGGGTT327GGAAUUATTGTTUTGUTGUUUAUAGUTGRGTGGAGGGATTURGGTUUTRGGGTTUAGTTGGTGAUAGTGTRGGGTAGGUUTGGGUAGGTGGGAGAGGTRGTGAAGUUUTTTGUAGGGUAUTTGGURGUTUATUTGGUAUAGGGGAAGAGGXGUAGUURGTGGUURGGUAGTUUAGGAUUTGUTGTTUUUTTUUTAUURGGGGRGGGGUUTGTGGGAAGATATGGAAGTRGGGTGAATGAGURGTGUUUAGTGATTTTAAAAAGUAGATTAAAATAAUATAGAAAATGTUAGAGUTUATTG328UAATGAGUTUTGAUATTTTUTATGTTATTTTAATUTGUTTTTTAAAATUAUTGGGUARGGUTUATTUAUURGAUTTUUATATUTTUUUAUAGGUUURGUUURGGGTAGGAAGGGAAUAGUAGGTUUTGGAUTGURGGGUUARGGGUTGXGUUTUTTUUUUTGTGUUAGATGAGRGGUUAAGTGUUUTGUAAAGGGUTTUARGAUUTUTUUUAUUTGUUUAGGUUTAUURGAUAUTGTUAUUAAUTGAAUURGAGGAURGGAATUUUTUUARGUAGUTGTGGGUAGUAGAAUAATGGTTUU329GUATUUTUAUUTGRGTURGAAGRGUAGATGGAGUUUAAGGGAAAGGUUUTGTAGAGGAUUURGTGTGAUTTGGGGUAAAGRGTGGUUTUUUAGGGGTGRGTGGGUAGRGGGARGUUUATGGTGTGAURGGGTTTGTGUUTUUATAGGGAUXGTUTGUUUTGTGUAGAGAGUUUUTGTGGGGXGGGAAGTGGXGAGUAGURGGUAAGGAGGUUUAGUUAGAUAGAAGUAGGGGGGTUAGGGAUATGGGAGGTGGGGGAUUAGUUAGTGAGTUAGARGTGAGGAUTTUAGTGUUAAGGAUTG330UAGTUUTTGGUAUTGAAGTUUTUARGTUTGAUTUAUTGGUTGGTUUUUUAUUTUUUATGTUUUTGAUUUUUUTGUTTUTGTUTGGUTGGGUUTUUTTGURGGUTGUTXGUUAUTTUUXGUUUUAUAGGGGUTUTUTGUAUAGGGUAGAXGGTUUUTATGGAGGUAUAAAUURGGTUAUAUUATGGGRGTUURGUTGUUUARGUAUUUUTGGGAGGUUARGUTTTGUUUUAAGTUAUARGGGGTUUTUTAUAGGGUUTTTUUUTTGGGUTUUATUTGRGUTTRGGARGUAGGTGAGGATGU331AGGTTUUUUATUUTAGUTUUURGGATUTUUATAGGGAGTGTUUAGGGAUUUTUAATUTUUAGGGUUAUTTUTGUAGGAGUTRGGGTTRGAGGTTUUARGTGGUUAGAAGAGUTUAGGTUTUTGAGGGUTGGTGTGUURGGGTAUUUATUXGUATUAUTGUTUTUUTUUTGTURGGUTARGUUUAGGGUTGAGTGARGGTGGTGGUAAGTGUTTGTUUTUAGGGUAGRGAGGTUTTUTGTTUTGAUAGUAGUAGGGAUTUUTTUATGGUUAUUAGTAAUUUUAGTGGGRGGAGGRGUTUUT332AGGAGRGUUTURGUUUAUTGGGGTTAUTGGTGGUUATGAAGGAGTUUUTGUTGUTGTUAGAAUAGAAGAUUTRGUTGUUUTGAGGAUAAGUAUTTGUUAUUAURGTUAUTUAGUUUTGGGRGTAGURGGAUAGGAGGAGAGUAGTGATGXGGATGGGTAUURGGGUAUAUUAGUUUTUAGAGAUUTGAGUTUTTUTGGUUARGTGGAAUUTRGAAUURGAGUTUUTGUAGAAGTGGUUUTGGAGATTGAGGGTUUUTGGAUAUTUUUTATGGAGATURGGGGAGUTAGGATGGGGAAUUT333TUUTTUUTTUTTTUUTTUTTTUTUTUTUTTTTUTTTUTTTTUTTTTUTTTTUTUTTUTTTUATTTTGAGARGTAUTUTGGUTUTGTRGUUUAGGUTGGAGRGUAATGGRGUUATUTRGGRGUAUTGUAAUUTUUAUUTUURGGGTTUAAGXGATTUTAUTGUUTUAGUUTUURGAGTAGUTGGGAUTAUAGGRGRGUAUTAUUAAGUURGGUTAATTTTTTTTTGTATTTTTAGTAGAGAUTGGGTTTUARGATGTTGGURGGGUTGGTUTGGAAGTUTTGAUUTUAAGRGTGRGUUUTU334GAGGGRGUARGUTTGAGGTUAAGAUTTUUAGAUUAGUURGGUUAAUATRGTGAAAUUUAGTUTUTAUTAAAAATAUAAAAAAAAATTAGURGGGUTTGGTAGTGRGRGUUTGTAGTUUUAGUTAUTRGGGAGGUTGAGGUAGTAGAATXGUTTGAAUURGGGAGGTGGAGGTTGUAGTGRGURGAGATGGRGUUATTGRGUTUUAGUUTGGGRGAUAGAGUUAGAGTARGTUTUAAAATGAAAGAAGAGAAAAGAAAAGAAAAGAAAGAAAAGAGAGAGAAAGAAGGAAAGAAGGAAGGA335AGGUUTUTGUTGAUUTGTAGAAUTTGTTGAUURGGATTTTGATGTUAGTUTUATTGGGUUTGURGTTGUTUTTUTTGGGAUAGAAGATUTUTTTGATURGGUUAATTRGGTAGGGUTUAGGGGUATUUAGGTTGUTGUUTTTGATGTAGTXGGAGTATTTURGGTAGTGUTUTGGGTAUAGGTUUTUATUUARGGGUTUUTTURGTGGGRGTTTUARGGGAUTGGAUAGUTTGATGUTGUAGAGAAGUAUUUAUTTGAUATUAATGAAUUTTUUAUUTTGUAGTGGTUAGTUAGGUATGA336TUATGUUTGAUTGAUUAUTGUAAGGTGGAAGGTTUATTGATGTUAAGTGGGTGUTTUTUTGUAGUATUAAGUTGTUUAGTUURGTGAAARGUUUARGGAAGGAGUURGTGGATGAGGAUUTGTAUUUAGAGUAUTAURGGAAATAUTUXGAUTAUATUAAAGGUAGUAAUUTGGATGUUUUTGAGUUUTAURGAATTGGURGGATUAAAGAGATUTTUTGTUUUAAGAAGAGUAARGGUAGGUUUAATGAGAUTGAUATUAAAATURGGGTUAAUAAGTTUTAUAGGTUAGUAGAGGUUT337GGGGRGGGGTTRGGURGGGGGRGGRGGUAGGAUUTGAGUAGUUAGGAGGGUTGGGGGAUAGTUAGGTUAGGURGGTGGUTAUURGGURGUTGGAGAGGGURGGATGGUARGTGGUAUUAAGUAAAAGGAGGUTGAGUUAGAAAGUAGGGAXGGGGUTAGARGAGUAAAGUTGGGUAGGAGGGRGAGTTGGGAGGGGURGAGURGGUTGTGRGTGGTUUUTTGGGAGGAGGGGGTGTGGUUAAGUAAGUUAAAUAGTTRGGAGGTUAGTGUAAGGAUAAGAUAGUUTGGGUAAARGAGUAG338UTGUTRGTTTGUUUAGGUTGTUTTGTUUTTGUAUTGAUUTURGAAUTGTTTGGUTTGUTTGGUUAUAUUUUUTUUTUUUAAGGGAUUARGUAUAGURGGUTRGGUUUUTUUUAAUTRGUUUTUUTGUUUAGUTTTGUTRGTUTAGUUUXGTUUUTGUTTTUTGGUTUAGUUTUUTTTTGUTTGGTGUUARGTGUUATURGGUUUTUTUUAGRGGURGGGTAGUUAURGGUUTGAUUTGAUTGTUUUUUAGUUUTUUTGGUTGUTUAGGTUUTGURGURGUUUURGGURGAAUUURGUUUU339RGAGTTGGGAGGGGURGAGURGGUTGTGRGTGGTUUUTTGGGAGGAGGGGGTGTGGUUAAGUAAGUUAAAUAGTTRGGAGGTUAGTGUAAGGAUAAGAUAGUUTGGGUAAARGAGUAGGGGRGGAGRGTGAGAGUAGAUTGUAURGGATXGUTUAGGUUAGUUUAAGUTGAAGAGGAAGGGGUAAGUTUUAGAAGUAGGGGRGGGGURGAUUAAUUTRGUAGATUTGUTGGGRGAAGAGUAGUAGUTGGGUUAGUURGATGUTGTGURGGGGUAGGTAGTUTRGGAGGUTGUUUAGGGGU340UUUUTGGGUAGUUTURGAGAUTAUUTGUUURGGUAUAGUATRGGGUTGGUUUAGUTGUTGUTUTTRGUUUAGUAGATUTGRGAGGTTGGTRGGUUURGUUUUTGUTTUTGGAGUTTGUUUUTTUUTUTTUAGUTTGGGUTGGUUTGAGXGATURGGTGUAGTUTGUTUTUARGUTURGUUUUTGUTRGTTTGUUUAGGUTGTUTTGTUUTTGUAUTGAUUTURGAAUTGTTTGGUTTGUTTGGUUAUAUUUUUTUUTUUUAAGGGAUUARGUAUAGURGGUTRGGUUUUTUUUAAUTRGU341AAUAGGUUUAAGUUTGTGGUAGGTGGGGGTUAUUUAGUUUAGGRGUTTUUUAUUUURGGGUUTGGGUUAGAAGUUUAGGAGUTGGUTGRGGGURGGTTUTUUUUUAUUUAUTUTGGGGATGUUTUAGGUUTGGGTTTURGUUTTAGUUTXGUUAGGUUUUAATGAGUUTUTGTTTGGUUTGTAGTUAATTGAURGGTTGGAUTTGGGGUAGGTGUTRGAGGAGUUUUAUTGAGGGAGGGUAGGTUTUTTGTGRGTAUTGTUUAGUAUATAUAGGAAATTTAGUATTTUTGUUUAUUUAGU342GUTGGGTGGGUAGAAATGUTAAATTTUUTGTATGTGUTGGAUAGTARGUAUAAGAGAUUTGUUUTUUUTUAGTGGGGUTUUTRGAGUAUUTGUUUUAAGTUUAAURGGTUAATTGAUTAUAGGUUAAAUAGAGGUTUATTGGGGUUTGGXGAGGUTAAGGRGGAAAUUUAGGUUTGAGGUATUUUUAGAGTGGGTGGGGGAGAAURGGUURGUAGUUAGUTUUTGGGUTTUTGGUUUAGGUURGGGGGTGGGAAGRGUUTGGGUTGGGTGAUUUUUAUUTGUUAUAGGUTTGGGUUTGTT343UUTGAUUUAUUUAAUTUTUUUAGGGGARGTGGGGGUAUTGGAGUUUUAUAURGUAGGRGGTAGUTUAATGUAUURGRGTRGGAGTTUUTUUUURGRGAGRGTGGUAAGGUTUAGGGAAGTUURGGGUUUUTGGGGAGGGGGUUTTGURGXGUATUUTGTXGUAGGAAURGURGGGUUUTTUUTTURGRGGGAAGXGGUTTGGURGAUUUURGUUUURGUURGGGUUTUTTGGGGGTTTURGGTGUURGGUUAURGTGGGGUTGGGGAUTGAAAGTGATGGGAUTGAAGATGGGGUTGGAA344TTUUAGUUUUATUTTUAGTUUUATUAUTTTUAGTUUUUAGUUUUARGGTGGURGGGUAURGGAAAUUUUUAAGAGGUURGGGRGGGGGRGGGGGTRGGUUAAGUXGUTTUURGRGGAAGGAAGGGUURGGRGGTTUUTGXGAUAGGATGXGRGGUAAGGUUUUUTUUUUAGGGGUURGGGAUTTUUUTGAGUUTTGUUARGUTRGRGGGGGAGGAAUTURGARGRGGGTGUATTGAGUTAURGUUTGRGGTGTGGGGUTUUAGTGUUUUUARGTUUUUTGGGAGAGTTGGGTGGGTUAGG345TATUUAAATGTGTTTTATATAAAATGAATRGTTTTUAGTGUAUTGAGGAAGTTTTUTATTTAAAGAAATUUTGUTGTGAAUTUTTTTGTGAAGAATGUTTTUUTAATGGAATTAGTUAUUAUTGAGTUATTTUTGUAAAUTTUAGGTTTGXGGTTTTGUUTAAGUAAGATUTGGURGGAGAAGTGAGATAAATTATAGATGTRGUTAATAAATTAUAGATTAUTUAAAGGUAAAAGAGGAAAGAAAAAAAAAAATTGAUTRGTGTATATGAAURGAATTGAGTUAGGGGTUTUUAURGGU346GURGGTGGAGAUUUUTGAUTUAATTRGGTTUATATAUARGAGTUAATTTTTTTTTTTUTTTUUTUTTTTGUUTTTGAGTAATUTGTAATTTATTAGRGAUATUTATAATTTATUTUAUTTUTURGGUUAGATUTTGUTTAGGUAAAAUXGUAAAUUTGAAGTTTGUAGAAATGAUTUAGTGGTGAUTAATTUUATTAGGAAAGUATTUTTUAUAAAAGAGTTUAUAGUAGGATTTUTTTAAATAGAAAAUTTUUTUAGTGUAUTGAAAARGATTUATTTTATATAAAAUAUATTTGGATA347TGGGAGTTUUAGTTRGGGGGUAGAUUAGTGTTUAGAGTURGGGUTUTGUTAUTUAGRGUURGAGGUAGRGUUTUUUUATTUAARGGGGGURGTGGUAATTUUUTGAUATGATTUATGAUUAUATAATAUATURGGAAAUTTUTUTUUAUXGUUTUURGTUTGGGURGTRGUUUURGGUUTGGGAGAUTUUAGGTUTUAGAGTUTUTGUUUUUARGGGRGATUAGTGUTGUUUAGTGGAAAAATAATGUUAGURGRGUAUUAAAATTAGGTGTAAAATTAAUATTTTTTGGAAGUUAUTTT348AAGTGGUTTUUAAAAAATGTTAATTTTAUAUUTAATTTTGGTGRGRGGUTGGUATTATTTTTUUAUTGGGUAGUAUTGATRGUURGTGGGGGUAGAGAUTUTGAGAUUTGGAGTUTUUUAGGURGGGGGRGARGGUUUAGARGGGAGGXGGTGGAGAGAAGTTTURGGATGTATTATGTGGTUATGAATUATGTUAGGGAATTGUUARGGUUUURGTTGAATGGGGAGGRGUTGUUTRGGGRGUTGAGTAGUAGAGUURGGAUTUTGAAUAUTGGTUTGUUUURGAAUTGGAAUTUUUAT349RGGRGTGUTTUTTGGUAAAUATUTUUTTGAGGATGURGUTGUAGUAUTTGAGUTGUTURGAGAUUTTGUTGUTUTTUTUTGGTGUTGGGTGUTGUTGAGAGTRGGGUARGTUUTTUTTTGGAGGTTTUAUAGGURGGUTGUTUTUURGUXGUTGGUUUAGUTTGGTGGTUTTGGGUTURGGGGGUAGRGAGGGTGGUTRGTGAATGGGGTUAATGGTGGTGGGGGTGGTGGTGTUTGUTTTUUTUTTUAUTUUUTTUTTTGTUTGUUAAGAAUARGGARGUUAAUAGGUAUAGTUAGAAG350UTTUTGAUTGTGUUTGTTGGRGTURGTGTTUTTGGUAGAUAAAGAAGGGAGTGAAGAGGAAAGUAGAUAUUAUUAUUUUUAUUAUUATTGAUUUUATTUARGAGUUAUUUTRGUTGUUUURGGAGUUUAAGAUUAUUAAGUTGGGUUAGXGGRGGGAGAGUAGURGGUUTGTGAAAUUTUUAAAGAAGGARGTGUURGAUTUTUAGUAGUAUUUAGUAUUAGAGAAGAGUAGUAAGGTUTRGGAGUAGUTUAAGTGUTGUAGRGGUATUUTUAAGGAGATGTTTGUUAAGAAGUARGURG351TGGTUTGUTTUAAGTUUTAUUTGGUUUUTGGUAAGTUUUAUTTGGTGAUATUTTGTGUUTGGGTUUTTGAGGGUTGUUUUAGATURGRGATTGTUUTGGGGAURGGTAGTTUUTUUURGGATGUUAGUAAAGUTUUUTUUAGUUTUUAXGUUTGUAUAGTUTUUAGTATGUUTTUAAUAGUUATTAGTUAUUUTUTGTGAGTUAGAUUUURGGTUUTGUUAGGUUAAUUTGUTTGGGGUUTUAGUAGRGGGGGUTGGRGAGGUUAGTTTTUTUUAGRGGTTUTAAGURGUTRGAGGGTGG352UAUUUTRGAGRGGUTTAGAAURGUTGGAGAAAAUTGGUUTRGUUAGUUUURGUTGUTGAGGUUUUAAGUAGGTTGGUUTGGUAGGAURGGGGGTUTGAUTUAUAGAGGGTGAUTAATGGUTGTTGAAGGUATAUTGGAGAUTGTGUAGGXGTGGAGGUTGGAGGGAGUTTTGUTGGUATURGGGGAGGAAUTAURGGTUUUUAGGAUAATRGRGGATUTGGGGUAGUUUTUAAGGAUUUAGGUAUAAGATGTUAUUAAGTGGGAUTTGUUAGGGGUUAGGTAGGAUTTGAAGUAGAUUAG353AUUTGGTRGGUUAURGGUAGUTRGGGGAAGAAGGGRGRGTGGRGRGUUUAUTUUARGGTGUTGAAGAGUAGURGRGURGUUAGUTRGUAUARGTTGTRGATGUUUAGUAURGRGUURGURGRGURGUUUUUTGRGURGAAGRGTURGGUXGURGUAGGGTAGGGUTUAGRGRGUAGUAGUTGRGRGATUAGTTRGGAUAURGGUTGUUURGGGAAGAGGTUTURGURGUTRGUUAUTGURGUUAGRGURGAGUURGGGGGGUTGUURGAGGAGGRGGUUARGGUAUUAGGUAGRGAGTGU354GUAUTRGUTGUUTGGTGURGTGGURGUUTUUTRGGGUAGUUUUURGGGUTRGGRGUTGGRGGUAGTGGRGAGRGGRGGAGAUUTUTTUURGGGGUAGURGGTGTURGAAUTGATRGRGUAGUTGUTGRGRGUTGAGUUUTAUUUTGRGGXGGURGGARGUTTRGGRGUAGGGGGRGGRGRGGRGGGRGRGGTGUTGGGUATRGAUAARGTGTGRGAGUTGGRGGRGRGGUTGUTUTTUAGUAURGTGGAGTGGGRGRGUUARGRGUUUTTUTTUUURGAGUTGURGGTGGURGAUUAGGT355TGGUAGAGATAUAAATTUUTGATGGUAGAGGAGGGAGAGAGAGTGTGGGTGARGATGAUAATTGAAUTGAGAUUUAAAGGAGGTAGGGGAGAUATATGGGRGTUTUTGGGAAGATGGTUUURGGGAAAGUAUAGUUTTTAGAUAGGUUUXGAGGUAGGAGUUTGTUTGAUTUAURGGAGGAGUTTGGAGGAGGUTGAGGTGGUUTAAGTRGATTAAGUAGGGTGGGGAGGGAAGAGGRGATGGTGURGTGAGAUUAAGUAGGGUUTTGAGGTUTGGGGGGAGAAUTTTGGUTTTTAUTUT356GAGTAAAAGUUAAAGTTUTUUUUUUAGAUUTUAAGGUUUTGUTTGGTUTUARGGUAUUATRGUUTUTTUUUTUUUUAUUUTGUTTAATRGAUTTAGGUUAUUTUAGUUTUUTUUAAGUTUUTURGGTGAGTUAGAUAGGUTUUTGUUTXGGGGUUTGTUTAAAGGUTGTGUTTTUURGGGGAUUATUTTUUUAGAGARGUUUATATGTUTUUUUTAUUTUUTTTGGGTUTUAGTTUAATTGTUATRGTUAUUUAUAUTUTUTUTUUUTUUTUTGUUATUAGGAATTTGTATUTUTGUUAG357AGAGGAGGGAGAGAGAGTGTGGGTGARGATGAUAATTGAAUTGAGAUUUAAAGGAGGTAGGGGAGAUATATGGGRGTUTUTGGGAAGATGGTUUURGGGAAAGUAUAGUUTTTAGAUAGGUUURGAGGUAGGAGUUTGTUTGAUTUAUXGGAGGAGUTTGGAGGAGGUTGAGGTGGUUTAAGTRGATTAAGUAGGGTGGGGAGGGAAGAGGRGATGGTGURGTGAGAUUAAGUAGGGUUTTGAGGTUTGGGGGGAGAAUTTTGGUTTTTAUTUTGAGGAAGGTGGGAGUUAUAGAGGUTT358AGUUTUTGTGGUTUUUAUUTTUUTUAGAGTAAAAGUUAAAGTTUTUUUUUUAGAUUTUAAGGUUUTGUTTGGTUTUARGGUAUUATRGUUTUTTUUUTUUUUAUUUTGUTTAATRGAUTTAGGUUAUUTUAGUUTUUTUUAAGUTUUTUXGGTGAGTUAGAUAGGUTUUTGUUTRGGGGUUTGTUTAAAGGUTGTGUTTTUURGGGGAUUATUTTUUUAGAGARGUUUATATGTUTUUUUTAUUTUUTTTGGGTUTUAGTTUAATTGTUATRGTUAUUUAUAUTUTUTUTUUUTUUTUTG359TGGGRGTUTUTGGGAAGATGGTUUURGGGAAAGUAUAGUUTTTAGAUAGGUUURGAGGUAGGAGUUTGTUTGAUTUAURGGAGGAGUTTGGAGGAGGUTGAGGTGGUUTAAGTRGATTAAGUAGGGTGGGGAGGGAAGAGGRGATGGTGUXGTGAGAUUAAGUAGGGUUTTGAGGTUTGGGGGGAGAAUTTTGGUTTTTAUTUTGAGGAAGGTGGGAGUUAUAGAGGUTTUTAGAUAGAAGAAGGAUAAGURGGAUTUAGGATAUUAGGGTGGGGGTATUTGTGGGGGATAAAGGGAGAA360TTUTUUUTTTATUUUUUAUAGATAUUUUUAUUUTGGTATUUTGAGTURGGUTTGTUUTTUTTUTGTUTAGAAGUUTUTGTGGUTUUUAUUTTUUTUAGAGTAAAAGUUAAAGTTUTUUUUUUAGAUUTUAAGGUUUTGUTTGGTUTUAXGGUAUUATRGUUTUTTUUUTUUUUAUUUTGUTTAATRGAUTTAGGUUAUUTUAGUUTUUTUUAAGUTUUTURGGTGAGTUAGAUAGGUTUUTGUUTRGGGGUUTGTUTAAAGGUTGTGUTTTUURGGGGAUUATUTTUUUAGAGARGUUUA361GGUTTTGTGAAAUUAAUUAGGAAGAATGAAAUAUAGAGUTGGTURGAUAUUUAGUTRGAGGGAGGGGGGURGGAAGUTTUTGGAAGTTGGUTGUUUUTAAGUAGGGGUUAUTUTAGUUUAUAAGGUUAAGTTGGUAGAGGUAGAXGAGGGGAUTUTGXGGUTUAAGTUARGGGUUAGGAGUURGUAGUTGURGGGUTGGAAAGGTUAGAGURGGUTUTGRGTUTGGUTGRGURGGUAAGAAGUUAUAATTARGUAGGUAAAAGAGUURGGGGATTAGUUUUAGUAUUTGGGAUUUTGAAT362ATTUAGGGTUUUAGGTGUTGGGGUTAATUUURGGGUTUTTTTGUUTGRGTAATTGTGGUTTUTTGURGGRGUAGUUAGARGUAGAGURGGUTUTGAUUTTTUUAGUURGGUAGUTGRGGGUTUUTGGUURGTGAUTTGAGUXGUAGAGTUUUUTXGTUTGUUTUTGUUAAUTTGGUUTTGTGGGUTAGAGTGGUUUUTGUTTAGGGGUAGUUAAUTTUUAGAAGUTTURGGUUUUUUTUUUTRGAGUTGGGTGTRGGAUUAGUTUTGTGTTTUATTUTTUUTGGTTGGTTTUAUAAAGUU363AGGUTGAARGGAATTGGGAGUAGAGUUUTGRGGTAGGAUAGAGAUTTRGUAAAGUURGGAGUAUAUAGUAGUAUUURGTUTTUTAAAGGAUAATTTTGGGAAAAUTUTTGUUTAATATTUTGGUAUTAAGGATUATTUTGTUAUATUUUXGUTUTGGAUTAUAAGUUTGUAAGUUUUATURGGGGUAGGGUTUUTUATTUUTGTGUAURGTGGAAGUUUTGTGUUTGUUUAGGGUUTGGUAUTTGTARGTAUTTGAAAAUUTRGTGTGGAGTAAAGAGAGGGGTGATGTGUAAAGGUUTT364AAGGUUTTTGUAUATUAUUUUTUTUTTTAUTUUAUARGAGGTTTTUAAGTARGTAUAAGTGUUAGGUUUTGGGUAGGUAUAGGGUTTUUARGGTGUAUAGGAATGAGGAGUUUTGUUURGGATGGGGUTTGUAGGUTTGTAGTUUAGAGXGGGGATGTGAUAGAATGATUUTTAGTGUUAGAATATTAGGUAAGAGTTTTUUUAAAATTGTUUTTTAGAAGARGGGGTGUTGUTGTGTGUTURGGGUTTTGRGAAGTUTUTGTUUTAURGUAGGGUTUTGUTUUUAATTURGTTUAGUUT365AGUUAGGUTAAAUUAGRGTGTUUUAATGAGGGGUUUTGGGUTGAGTGGAGGAAATGGGTGRGGTGGAGGTGGGTTTGGUTGGGUAUAGRGGGUARGTGTGGGTAAGRGGGTGGGGURGGTTGTGRGGGTGGUUTATUTGGGGUAAGUAGUXGAGGURGAUTGTGTURGGRGTGTGGTTGAGUARGGGUAGGTGTUTGGRGGTGAUUUTGUARGTUTGGTGTTTAUUTGGUUUTGGGTUTGARGTGGGURGRGUUTGGUTGUTGGRGGGAUAGTGTGTTATUTGUUTGRGGARGUTTURGG366URGGAAGRGTURGUAGGUAGATAAUAUAUTGTUURGUUAGUAGUUAGGRGRGGUUUARGTUAGAUUUAGGGUUAGGTAAAUAUUAGARGTGUAGGGTUAURGUUAGAUAUUTGUURGTGUTUAAUUAUARGURGGAUAUAGTRGGUUTXGGUTGUTTGUUUUAGATAGGUUAUURGUAUAAURGGUUUUAUURGUTTAUUUAUARGTGUURGUTGTGUUUAGUUAAAUUUAUUTUUAURGUAUUUATTTUUTUUAUTUAGUUUAGGGUUUUTUATTGGGAUARGUTGGTTTAGUUTGGUT367UUTTGGUTUAGGTTGGGGAGGGRGTUATGAGTUATGAGGTGGGRGTTGUATTTGTUAGTTGTGUAGURGRGUAUUAURGAGTAGTUTGGRGGUAGRGRGTURGRGTTRGATTGRGTUTGGUURGUAGGAGGUURGGTUUAGUAGUUUTTUXGUAUUAGGGTUAURGGRGRGRGATAUUUTGGGGGRGGGATRGGGGUTRGTGUTUTGUTTUURGAAAUUUTTUTUUUTUUAGTUTUAGRGTTUTTUUTUUTUUUTUTATUUTTTUAUTTTUAUUTAUAUUTUUTUUUUTUUUTUUTTUUU368GGGAAGGAGGGAGGGGAGGAGGTGTAGGTGAAAGTGAAAGGATAGAGGGAGGAGGAAGAARGUTGAGAUTGGAGGGAGAAGGGTTTRGGGAAGUAGAGUARGAGUUURGATUURGUUUUUAGGGTATRGRGRGURGGTGAUUUTGGTGXGGAAGGGUTGUTGGAURGGGUUTUUTGRGGGUUAGARGUAATRGAARGRGGARGRGUTGURGUUAGAUTAUTRGGTGGTGRGRGGUTGUAUAAUTGAUAAATGUAARGUUUAUUTUATGAUTUATGARGUUUTUUUUAAUUTGAGUUAAGG369UAGGUTGGAGTGUAATGGRGRGATUTRGGUTUAUTGUAAUTTUTGUUTUTRGGGTTUAAGUAATTUTTUTAUUTTAGUUTUUTGAGTAGUTGGGATTAUAGGTAUUTGURGUUATGUURGGUTAATTTTTTAATTTGTTTTTAGTAGAGAXGGGGTTTUAUUATGTTGGUUAGGURGGTUTAUAAUTUUTGATUTUAGGTGATUTAUURGUUTRGGUUTUUUAAATTAUAGGTGTTATUATTAGGATTUTTGGUAGAUAGGAGTGTTGTAGGGGATGGAAGTGGATAGTAGGAGGUTUTG370UAGAGUUTUUTAUTATUUAUTTUUATUUUUTAUAAUAUTUUTGTUTGUUAAGAATUUTAATGATAAUAUUTGTAATTTGGGAGGURGAGGRGGGTAGATUAUUTGAGATUAGGAGTTGTAGAURGGUUTGGUUAAUATGGTGAAAUUUXGTUTUTAUTAAAAAUAAATTAAAAAATTAGURGGGUATGGRGGUAGGTAUUTGTAATUUUAGUTAUTUAGGAGGUTAAGGTAGAAGAATTGUTTGAAUURGAGAGGUAGAAGTTGUAGTGAGURGAGATRGRGUUATTGUAUTUUAGUUTG371TGAATGAUUTGGGUAGUATTTUTUUAUUTGRGUTTGUATTTGUTAGAUAGTUTGTGAUTUTUTGTGGGAGAAAAUAUAAGAAAURGGUUUUTUTGUTGGTTUUUUAUUTGGUUTGGUTUTUUTGTTUTUUAUUUTGUAUAUTUATGUUTXGGAAUUTGUTTUTUUTUTGAGUUTUUUTUAUAGTGGUURGGUUUARGTGGUUTTTAATUTGUUUAUATUAGAGUUTUUAUUTURGGUUTATGGUUUATUAGAGGUAGUTGGAGURGGGUATUUTUUUUARGTGGGUUTTTGAGGATGGGA372TUUUATUUTUAAAGGUUUARGTGGGGAGGATGUURGGUTUUAGUTGUUTUTGATGGGUUATAGGURGGAGGTGGAGGUTUTGATGTGGGUAGATTAAAGGUUARGTGGGURGGGUUAUTGTGAGGGAGGUTUAGAGGAGAAGUAGGTTUXGAGGUATGAGTGTGUAGGGTGGAGAAUAGGAGAGUUAGGUUAGGTGGGGAAUUAGUAGAGGGGURGGTTTUTTGTGTTTTUTUUUAUAGAGAGTUAUAGAUTGTUTAGUAAATGUAAGRGUAGGTGGAGAAATGUTGUUUAGGTUATTUA373GGGRGGGGUUTGTGRGGTUTGRGGRGRGGAGURGAGTGGGUTGRGGGGATGRGGGGGAUUAGUTGRGTGGGRGGRGGRGURGAGAGUUURGGAGGRGRGGGGUTGAGRGAGGGUURGRGGGGGRGUTGGUTGRGUTTGGUTURGGTATGXGUUTAUTTUUTUTGRGTUTXGUTAGUTGURGTGUTGUTRGURGTGTAUTARGGTUTUATUTGGGTAUUUARGRGGTUTUURGRGGUAUURGURGGUUUAUAGUUUAGRGRGURGTUUUUTURGTGTGUTGUURGUURGGGRGTGURGUUT374AGGRGGUARGUURGGGRGGGUAGUAUARGGAGGGGARGGRGRGUTGGGUTGTGGGURGGRGGGTGURGRGGGAGAURGRGTGGGTAUUUAGATGAGAURGTAGTAUARGGRGAGUAGUARGGUAGUTAGXGAGARGUAGAGGAAGTAGGXGUATAURGGAGUUAAGRGUAGUUAGRGUUUURGRGGGUUUTRGUTUAGUUURGRGUUTURGGGGUTUTRGGRGURGURGUUUARGUAGUTGGTUUUURGUATUUURGUAGUUUAUTRGGUTURGRGURGUAGAURGUAUAGGUUURGUUU375AAGTGTATTTTUAAGGTATGAGGGGUUUAGAGGAUAUTGTUUUAAAAGUAGTGGTTGTGAGAGTGGUTTTGGAGTUAGGUTGAUAGTUTGGAAAUTTUUAGGTURGUTUTGAAGTGURGGUTGUATGAUUAGUUUTUUAGUUTGTGTUXGUTTRGGUUTTUTTTGTGUAAGTGAGAGUATTGUTGATUUUUURGGGGTGGRGAGGGGGRGUARGTUAGTGAUUTRGUATGGTGUUTGUUAGGUARGTGGTURGTGTTTUATGATTUTTTGAGAGUTTTGGAGUAGUTUUAAGAAGAUTUT376GAGTUTTUTTGGAGUTGUTUUAAAGUTUTUAAAGAATUATGAAAUARGGAUUARGTGUUTGGUAGGUAUUATGRGAGGTUAUTGARGTGRGUUUUUTRGUUAUUURGGGGGGATUAGUAATGUTUTUAUTTGUAUAAAGAAGGURGAAGXGGAUAUAGGUTGGAGGGUTGGTUATGUAGURGGUAUTTUAGAGRGGAUUTGGAAGTTTUUAGAUTGTUAGUUTGAUTUUAAAGUUAUTUTUAUAAUUAUTGUTTTTGGGAUAGTGTUUTUTGGGUUUUTUATAUUTTGAAAATAUAUTTT377TAATTTTAAAUAAAAUTUTUUATGAGUAAUTAAATATTTAAAATGTGTTTTTUUATAAAAGTGAATUAGUTUAGTTUTGUAGGUTGAAAATAUAAUAAGGAGGATURGGGTTGUAGAAAGUAGAGGGUUAUUTAGAURGTGTUTGAGAGAXGGGGAGAAAGUAGUTGTUTGUTGTGUAUUAGAGGUUTUTAGGGAUUURGGUAGUAAUUURGTGGRGGGUUAUAUTTGGGAGUTGATTTGTTTTUAGAAUUAUUAGUTAAGUUAUATGAGUUAGGAGUUTGGTTATUUATTUAAAGUUUA378TGGGUTTTGAATGGATAAUUAGGUTUUTGGUTUATGTGGUTTAGUTGGTGGTTUTGAAAAUAAATUAGUTUUUAAGTGTGGUURGUUARGGGGTTGUTGURGGGGTUUUTAGAGGUUTUTGGTGUAUAGUAGAUAGUTGUTTTUTUUUXGTUTUTUAGAUARGGTUTAGGTGGUUUTUTGUTTTUTGUAAUURGGATUUTUUTTGTTGTATTTTUAGUUTGUAGAAUTGAGUTGATTUAUTTTTATGGAAAAAUAUATTTTAAATATTTAGTTGUTUATGGAGAGTTTTGTTTAAAATTA379GUUTUUAGAUURGAAATUUUUUAUTGAAGUUATTUUUAGGAGGAGGGGUUTUAUTGGGGUUTUAAGGUAGUATUAGUATTTURGGTGAUAGGUAUAGUAATTTATUAGUTUAUTGGUTUTUTAUTGAGAAUAAGGUAAGURGGGGUUTGUXGAGGGTATGAUAGGUAGGGAGTGATGGGUURGGUUUAGGGUAGGAGGGAGAUAGAAATGGGUAGGAAGAGGAGGUTGTUUUUAGUAGUAUTTUTGAGAGGAGGAGUAUUTTTRGGGGAUAUTUTGGARGGUAUUUUUAAGUAUAGUUUU380GGGGUTGTGUTTGGGGGTGURGTUUAGAGTGTUUURGAAAGGTGUTUUTUUTUTUAGAAGTGUTGUTGGGGAUAGUUTUUTUTTUUTGUUUATTTUTGTUTUUUTUUTGUUUTGGGURGGGUUUATUAUTUUUTGUUTGTUATAUUUTXGGUAGGUUURGGUTTGUUTTGTTUTUAGTAGAGAGUUAGTGAGUTGATAAATTGUTGTGUUTGTUAURGGAAATGUTGATGUTGUUTTGAGGUUUUAGTGAGGUUUUTUUTUUTGGGAATGGUTTUAGTGGGGGATTTRGGGTUTGGAGGU381TGAGAGUAGUUAGAUARGTAGTGATUAGGGAAAGTRGAAAGTGUAGATGGGTTRGUAAARGTGGAUTUTUTAGTTTTGGGTUTGUAGATGGGGURGGUUAUUAXGTGUTUTUTGAGTTUTUTTTUUAAGTAUAGATUUUTURGGAGARGGAAUATTGTTURGUUTTTAATTUTTUUUAGGAGUTGRGGAGGAAGGXGTGAGAAURGGAGUURGGGGTGAUTTGRGGGGGAGGGGATRGUTTUUURGTRGUUUAUAUUTGUUTAAUUUARGUUUARGGRGGURGUAAAGGRGAUAURGRGT382ARGRGGTGTRGUUTTTGRGGURGURGTGGGRGTGGGTTAGGUAGGTGTGGGRGARGGGGAAGRGATUUUUTUUUURGUAAGTUAUUURGGGUTURGGTTUTUAXGUUTTUUTURGUAGUTUUTGGGAAGAATTAAAGGRGGAAUAATGTTURGTUTURGGAGGGATUTGTAUTTGGAAAGAGAAUTUAGAGAGUAXGTGGTGGURGGUUUUATUTGUAGAUUUAAAAUTAGAGAGTUUARGTTTGRGAAUUUATUTGUAUTTTRGAUTTTUUUTGATUAUTARGTGTUTGGUTGUTUTUA383AUAAGRGGTTGGATTTRGAGAGGAUATUAAGAGUARGTUAAGAGUARGTUAAGAGUAUARGGAUAGGUAUTGGUARGURGGUAGGTUATTGAURGGUAGAAUAGAGTTTGGUUAGGGUTGTUAGAGAAGAGTRGGGURGUUAAGUAGUUXGAUTTUUAGRGGAAAAUUATUTGUUTTUTGGUTUUTUUATUTGUTGAGAGUTAUTTUUAUTUAATAAAAUUTTGUAUTUATTUTUUAAAUUUAUATGAGATUUAATTUTTURGGTAUAUUAAGGUAGGAAUUURGAGATAUAGAAAGUUU384GGGUTTTUTGTATUTRGGGGTTUUTGUUTTGGTGTAURGGAAGAATTGGATUTUATGTGGGTTTGGAGAATGAGTGUAAGGTTTTATTGAGTGGAAGTAGUTUTUAGUAGATGGAGGAGUUAGAAGGUAGATGGTTTTURGUTGGAAGTXGGGUTGUTTGGRGGUURGAUTUTTUTUTGAUAGUUUTGGUUAAAUTUTGTTUTGURGGTUAATGAUUTGURGGRGTGUUAGTGUUTGTURGTGTGUTUTTGARGTGUTUTTGARGTGUTUTTGATGTUUTUTRGAAATUUAAURGUTTGT385AUTTGAAGTUAGGAGTTRGTGAAUAGUUTGGUUAAUATGGTGAAAUUUTGTUTUTAUTAAAAAAAGAAAAATTAGURGGGTGTGGTGGGRGUUTGTAAUUUUAGUAUTTTGGGAGGUTGAGGTGGGTGGATUAUTTGAAGTUAGGAGTTXGTGAAUAGUUTGATUAAUATGGTGAAAUUUTGTUTUTAUTAAAAAUAUAAAAATTAGURGGGTGTGGTGGTGGGTGUUTGTAATUUUAGUTAUTUAGGAGAUTGAGGUAGGAGGATUAUTTGAAURGGGGAGGUAGAGGTTGUAGAGAGT386UTUTUTGUAAUUTUTGUUTUUURGGTTUAAGTGATUUTUUTGUUTUAGTUTUUTGAGTAGUTGGGATTAUAGGUAUUUAUUAUUAUAUURGGUTAATTTTTGTGTTTTTAGTAGAGAUAGGGTTTUAUUATGTTGATUAGGUTGTTUAXGAAUTUUTGAUTTUAAGTGATUUAUUUAUUTUAGUUTUUUAAAGTGUTGGGGTTAUAGGRGUUUAUUAUAUURGGUTAATTTTTUTTTTTTTAGTAGAGAUAGGGTTTUAUUATGTTGGUUAGGUTGTTUARGAAUTUUTGAUTTUAAGTG387AAATUTTTTTUUTGUUTGUATTTTUTTAUATAAAGUAATUTAUTAUTGUUATRGGTTUATTUAUTUAURGGAAUUTGTUTTGUUAGGAUUTGAUUTUAGUAGAUTGAGTUATAUUAGUATUATUUTTGTTGGGGUUUAGGTUTGUATUUXGUTTURGGUUUUAGUUUUAUTGTTAGUTUUATUAGGTUUTUTGGGGUAUAUUAAGGAGGURGTTTTUTUTUUUTTTTTUTGAATTAGATUUUUAGAAAUAAGAUATUAGGUTTUUTGGGGAAATUTAATTTTGUTUATGAATTTGAUUAT388ATGGTUAAATTUATGAGUAAAATTAGATTTUUUUAGGAAGUUTGATGTUTTGTTTUTGGGGATUTAATTUAGAAAAAGGGAGAGAAAARGGUUTUUTTGGTGTGUUUUAGAGGAUUTGATGGAGUTAAUAGTGGGGUTGGGGURGGAAGXGGGATGUAGAUUTGGGUUUUAAUAAGGATGATGUTGGTATGAUTUAGTUTGUTGAGGTUAGGTUUTGGUAAGAUAGGTTURGGTGAGTGAATGAAURGATGGUAGTAGTAGATTGUTTTATGTAAGAAAATGUAGGUAGGAAAAAGATTT389UAAGGTUUAGGTUUUAGUUTUUUUAURGURGUURGRGUUUTUUTAGGUUTRGGAGRGGRGUUTTTUTGRGGUUTRGAAGGTGGGGTGGGAAAGTTTGGGGAGTUURGGUTUTUAUAGUUTGTRGTGAGAAUTGUUUURGGGGAATTRGTUXGURGTARGGAAAAAUTGGURGGAGUAGAGTRGTURGRGGTTURGRGGTRGRGGGTGGAAGGTGAAGGTRGAGGGAGGTUAGGUTGUTTUTGRGTGTUUTGARGGUTGGRGTGTTUTUTTGAGATGGGUTRGGGUTAUTTGGUUAGUTTU390GAAGUTGGUUAAGTAGUURGAGUUUATUTUAAGAGAAUARGUUAGURGTUAGGAUARGUAGAAGUAGUUTGAUUTUUUTRGAUUTTUAUUTTUUAUURGRGAURGRGGAAURGRGGARGAUTUTGUTURGGUUAGTTTTTURGTARGGXGGARGAATTUUURGGGGGUAGTTUTUARGAUAGGUTGTGAGAGURGGGAUTUUUUAAAUTTTUUUAUUUUAUUTTRGAGGURGUAGAAAGGRGURGUTURGAGGUUTAGGAGGGRGRGGGRGGRGGTGGGGAGGUTGGGAUUTGGAUUTTG391URGAGGGAGUUAGGUUAUAGUTGAUAGGAAGGUAGAAGGTGGUAGGAGGGGAGGTTGRGUTGUAUUTUTGGGTTGUUUAGGUUAAUUTGUUAGGUAGGAGGGGGAAGUURGTGUUUAUTTTAUUATGAURGGGAAGATGATGGUAGUUAUXGTGGATTTGAGGATUUAGAGUAURGUUAGGUAGAGGATUTGUAUUAGGGTGAAGAGGTGGATURGGRGUAGRGGUARGTGURGUAGGAAGGUATGGTURGGUTGGTGUTTGGUTGGUATUAGGAAGAGUTTGUAGRGTTUUUAGAAUTA392TAGTTUTGGGAARGUTGUAAGUTUTTUUTGATGUUAGUUAAGUAUUAGURGGAUUATGUUTTUUTGRGGUARGTGURGUTGRGURGGATUUAUUTUTTUAUUUTGGTGUAGATUUTUTGUUTGGRGGTGUTUTGGATUUTUAAATUUAXGGTGGUTGUUATUATUTTUURGGTUATGGTAAAGTGGGUARGGGUTTUUUUUTUUTGUUTGGUAGGTTGGUUTGGGUAAUUUAGAGGTGUAGRGUAAUUTUUUUTUUTGUUAUUTTUTGUUTTUUTGTUAGUTGTGGUUTGGUTUUUTRGG393AAATTAUURGGGRGTGGTGGTGGGTGUUTGTAATUUUAGUTAUTUAGGAGGURGAGGUAGGAGAAURGUTTGAAUURGGGAGGUAGAGUATAGGTTGTTGGAGGGTTGAAGGTGUAUUUAGUAGAGAUTGGUATAUAGGAGGTUUTGUAAXGGUUUUAGGAAAUUTUTGGGTUUAGTAAGAGUTTUAGUAGGAGGTAGAAUUATAURGGGUAGGAGTGUUTGGAAAGGUTTUAAGGUAAUTUUUTUUAAAGTUUTGGUUUAAUUUTAUAUTGTUAGGUTGTTAAAGGUUATTTAAAAGUT394AGUTTTTAAATGGUUTTTAAUAGUUTGAUAGTGTAGGGTTGGGUUAGGAUTTTGGAGGGAGTTGUUTTGAAGUUTTTUUAGGUAUTUUTGUURGGTATGGTTUTAUUTUUTGUTGAAGUTUTTAUTGGAUUUAGAGGTTTUUTGGGGUXGTTGUAGGAUUTUUTGTATGUUAGTUTUTGUTGGGTGUAUUTTUAAUUUTUUAAUAAUUTATGUTUTGUUTUURGGGTTUAAGRGGTTUTUUTGUUTRGGUUTUUTGAGTAGUTGGGATTAUAGGUAUUUAUUAUUARGUURGGGTAATTT395AGGAAAAAAUAGUAGUUUAAGAATRGGGUUTUUUTGTTAUAGUAGGAGTRGUATUTATTTATATATGTTATGTUTTATTGUTUAGUAAUUAGUTUTRGGURGGGGRGTGGGURGGGAAGAGGGGTUTUUTGGTGUAGXGGGTTGGRGTGAUTUATUAURGURGXGUAUTUTGGUUTUTGGGUUTAGGTTAAUAGAUTUURGGGTTTUAGGUTGGGUUUAGGRGGUUAGGUUUTUUUTGUTGAGGAATUTGGGTTGGGGUAGTGUUAGUTUUUTGUTTUTUAUUTGGUUAUAGAAGGGGTA396TAUUUUTTUTGTGGUUAGGTGAGAAGUAGGGAGUTGGUAUTGUUUUAAUUUAGATTUUTUAGUAGGGAGGGUUTGGURGUUTGGGUUUAGUUTGAAAUURGGGAGTUTGTTAAUUTAGGUUUAGAGGUUAGAGTGXGRGGRGGTGATGAGTUARGUUAAUUXGUTGUAUUAGGAGAUUUUTUTTUURGGUUUARGUUURGGURGAGAGUTGGTTGUTGAGUAATAAGAUATAAUATATATAAATAGATGRGAUTUUTGUTGTAAUAGGGAGGUURGATTUTTGGGUTGUTGTTTTTTUUT397AUUUAGGAATTUTTTTTTTTTTTTTTTTGAGARGGRGTUTUTGTRGUUUAGGUTGGAGTGUAGTGGRGUAGTUTRGUUTAAUTGUAAGUTURGUUUURGGGTTUATGUUATTUTUUTGUUTUAGUUTUTTGAGTAGUTGGAAUTAUAGGXGUUTGUUAUUAUAUURGGUUAATTTTTTGTATTTTTAGTAGAGARGGGGTTTUAURGTGTTAGUUAGGATGGTUTRGATUTUUTGAUUTRGTGATUUAUUUAUUTUAGUUTUTUAAAGTGUTGGGATTAUAGGUTTGAAUUAUTGRGUUU398GGGRGUAGTGGTTUAAGUUTGTAATUUUAGUAUTTTGAGAGGUTGAGGTGGGTGGATUARGAGGTUAGGAGATRGAGAUUATUUTGGUTAAUARGGTGAAAUUURGTUTUTAUTAAAAATAUAAAAAATTGGURGGGTGTGGTGGUAGGXGUUTGTAGTTUUAGUTAUTUAAGAGGUTGAGGUAGGAGAATGGUATGAAUURGGGGGRGGAGUTTGUAGTTAGGRGAGAUTGRGUUAUTGUAUTUUAGUUTGGGRGAUAGAGARGURGTUTUAAAAAAAAAAAAAAAAGAATTUUTGGGT399AAATAUAGUAGGAGAGAATTUUTUTGAGAUUTAAGATAURGTGUUUTTUUUUUTTGGUUTUTUAGUTGUTGURGAGTUUTGGAGAAAATRGGGUATUTGAAUAGAGGURGTGTTTGTUUUTGUTURGGUUTTGTGTTUTUATTUUTGUUAXGUUATUATGGATAATGAAAGTTGAUTGGUTGURGGGGTTTUUTTTUTUTUTGUUUUTGTUATTTUUATTTGUUAGGTUTUATGUUTTTTTTGUAUAGAGTTGTTGTGUTTGGGUTUTAATTTGUUAGGUAGTGATAAATTUUAAGAAAA400TTTTUTTGGAATTTATUAUTGUUTGGUAAATTAGAGUUUAAGUAUAAUAAUTUTGTGUAAAAAAGGUATGAGAUUTGGUAAATGGAAATGAUAGGGGUAGAGAGAAAGGAAAUUURGGUAGUUAGTUAAUTTTUATTATUUATGATGGXGTGGUAGGAATGAGAAUAUAAGGURGGAGUAGGGAUAAAUARGGUUTUTGTTUAGATGUURGATTTTUTUUAGGAUTRGGUAGUAGUTGAGAGGUUAAGGGGGAAGGGUARGGTATUTTAGGTUTUAGAGGAATTUTUTUUTGUTGTATTT401GUUUTGAGAUAUTAAATGGRGGGGGGGTGGGGGGAGGAAAGGGAAGGRGGUAGAGUTUUURGAGURGGGAUAGTUAUTTAUTUTAUAGGUAGTGGGGUURGAUAUAGAUAGRGURGUUUURGUUAGUUAGUUTRGUARGUUUTRGGAAGXGUAGGUTUURGGRGUTGRGUTGGAGGGTTUUURGGUAUUUUAGUUTUURGTUUUUAGUURGUTGUAUUTURGGGUUUUUUTTAUUUTTGAGAGGUAURGGGAGTTGTRGRGGGGGGGUUTRGGGAAATTUUURGGAUUUUTGTGUUAGGA402TUUTGGUAUAGGGGTURGGGGAATTTUURGAGGUUUUUURGRGAUAAUTUURGGTGUUTUTUAAGGGTAAGGGGGGUURGGAGGTGUAGRGGGUTGGGGARGGGAGGUTGGGGTGURGGGGAAUUUTUUAGRGUAGRGURGGGAGUUTGXGUTTURGAGGGRGTGRGAGGUTGGUTGGRGGGGGRGGRGUTGTUTGTGTRGGGUUUUAUTGUUTGTAGAGTAAGTGAUTGTUURGGUTRGGGGAGUTUTGURGUUTTUUUTTTUUTUUUUUUAUUUUUURGUUATTTAGTGTUTUAGGGU403AUUAUAGUAUTGUAGGAGGATGAGUUUUTGUAGGAAGGAATGUTGGUTUTUTGGGGTAGATAAAGAAGGTTUTGGGGAAGGGAAGGGAGGAAUAGGAAUATGGGUTUUUTGUUAGGUTGTUUUAGGTURGGGATGUUATRGGUAAGTGGGXGGGGAUAGGUUTGGGTAGATGAUATGGTAGTGAGTAAGTGGGGAGGUAGGUUAGUAGAGGAGUUAGGUTUAUUTUUXGUUXGUUUAUUTRGGUUAUAGAURGGGAGGGGTRGGAGUAUTGRGTTGGGGTTGATGAGUAGARGAUTGUUA404TGGUAGTRGTUTGUTUATUAAUUUUAARGUAGTGUTURGAUUUUTUURGGTUTGTGGURGAGGTGGGXGGGXGGGAGGTGAGUUTGGUTUUTUTGUTGGUUTGUUTUUUUAUTTAUTUAUTAUUATGTUATUTAUUUAGGUUTGTUUUXGUUUAUTTGURGATGGUATUURGGAUUTGGGAUAGUUTGGUAGGGAGUUUATGTTUUTGTTUUTUUUTTUUUTTUUUUAGAAUUTTUTTTATUTAUUUUAGAGAGUUAGUATTUUTTUUTGUAGGGGUTUATUUTUUTGUAGTGUTGTGGT405AGGGAAGGGAGGAAUAGGAAUATGGGUTUUUTGUUAGGUTGTUUUAGGTURGGGATGUUATRGGUAAGTGGGXGGGGAUAGGUUTGGGTAGATGAUATGGTAGTGAGTAAGTGGGGAGGUAGGUUAGUAGAGGAGUUAGGUTUAUUTUUXGUUXGUUUAUUTRGGUUAUAGAURGGGAGGGGTRGGAGUAUTGRGTTGGGGTTGATGAGUAGARGAUTGUUAGGUAGUUATTUAUAGGAAATGGUAUAGARGUAUATTGTTUUAGUTAUUUUUUATUUTUUUTUAGGGGUAAAGTGAATG406ATTUAUTTTGUUUUTGAGGGAGGATGGGGGGTAGUTGGAAUAATGTGRGTUTGTGUUATTTUUTGTGAATGGUTGUUTGGUAGTRGTUTGUTUATUAAUUUUAARGUAGTGUTURGAUUUUTUURGGTUTGTGGURGAGGTGGGXGGGXGGGAGGTGAGUUTGGUTUUTUTGUTGGUUTGUUTUUUUAUTTAUTUAUTAUUATGTUATUTAUUUAGGUUTGTUUUXGUUUAUTTGURGATGGUATUURGGAUUTGGGAUAGUUTGGUAGGGAGUUUATGTTUUTGTTUUTUUUTTUUUTT407GGTTUTAAAUAUAUAAAUUTTTGATGUATUTGGAATTTAUUTTAATTTUUTAGUAATTTTTATUAATGGUTUAATATTTGGGGGATTTTUATGGTAATTGUAUTGAATGTATTAAUTGGTUAGGGAGGATTAUATUAAGAUUAURGGUTXGAGAAAUAGUAGTUTGTTUUTUUAUUUUUARGTUTGUATUUAGGUUUTTUUAUAGAGATUTUATTTUTUUTGUAGATGAUTUATTUAGTGTUTAGGAATURGGTGUTUTGTGGUUAUTAURGAGAGTGGGATATTTTUUUUUATTTTATT408AATAAAATGGGGGAAAATATUUUAUTUTRGGTAGTGGUUAUAGAGUAURGGATTUUTAGAUAUTGAATGAGTUATUTGUAGGAGAAATGAGATUTUTGTGGAAGGGUUTGGATGUAGARGTGGGGGTGGAGGAAUAGAUTGUTGTTTUTXGAGURGGTGGTUTTGATGTAATUUTUUUTGAUUAGTTAATAUATTUAGTGUAATTAUUATGAAAATUUUUUAAATATTGAGUUATTGATAAAAATTGUTAGGAAATTAAGGTAAATTUUAGATGUATUAAAGGTTTGTGTGTTTAGAAUU409TTTGGGGGGUAGGGAGGGTTUAGTUUUUTUAGGUUTGGUTGTGTUUUUTGUUUUUUAUUUAUAATUAGGUUUAGGGTTGGGGGGTGUAUAUUAAGGAGGGGUAGGAAGTGTUUAAGAAGUAGAAURGGUTUTGTGTUUUUAGTGGXGGXGGGTGTUTGGGGUAGGAGGAGGUTATUTGATUUUTTUUUUAUTGUUURGGUUATGAUUTUUTUUUTUUUTUUUTRGUTUUUTUUUTUUUTUUUTUUUTUUUTUUUTUUUTUUUTUUTUUTTUATGGUTGGGGTAGUUAGUAUUUTGGGUTG410AGUUUAGGGTGUTGGUTAUUUUAGUUATGAAGGAGGAGGGAGGGAGGGAGGGAGGGAGGGAGGGAGGGAGGGAGRGAGGGAGGGAGGGAGGAGGTUATGGURGGGGUAGTGGGGAAGGGATUAGATAGUUTUUTUUTGUUUUAGAUAUUXGUXGUUAUTGGGGAUAUAGAGURGGTTUTGUTTUTTGGAUAUTTUUTGUUUUTUUTTGGTGTGUAUUUUUUAAUUUTGGGUUTGATTGTGGGTGGGGGGUAGGGGAUAUAGUUAGGUUTGAGGGGAUTGAAUUUTUUUTGUUUUUUAAAG411UURGUAAGUUTRGUUUUTUUAGGUUTRGUUUTUUUTUUTTGUAGAGAGTGGUUAAGUTRGTGTTUUAGAGGUTGAATGAGGATTTTGTGRGGAAGUURGAUTATGUTTTGAGUTUTGTGGGTAAGAUURGGAGAUAUTGGAAGAUAGAGAXGUAGAUAGGAAAGAGGUUAAGAUAUTGAUAUAGAUAGAUUUATGUAUUTGAURGGURGAAGAUAGAGUUTRGGAUAGUUUUUAUURGUUUUUAGUUUURGRGUUUURGRGUUURGAUTUURGGUAAGGUUTGGGAGUUTUTGAGGGTTA412TAAUUUTUAGAGGUTUUUAGGUUTTGURGGGAGTRGGGGRGRGGGGGRGRGGGGGUTGGGGGRGGGTGGGGGUTGTURGAGGUTUTGTUTTRGGURGGTUAGGTGUATGGGTUTGTUTGTGTUAGTGTUTTGGUUTUTTTUUTGTUTGXGTUTUTGTUTTUUAGTGTUTURGGGTUTTAUUUAUAGAGUTUAAAGUATAGTRGGGUTTURGUAUAAAATUUTUATTUAGUUTUTGGAAUARGAGUTTGGUUAUTUTUTGUAAGGAGGGAGGGRGAGGUUTGGAGGGGRGAGGUTTGRGGG413UAGATUAGGGTUUTUAGAUTTGTURGGAGGGAGGGUUUTGUATAUUTGUUAARGUUUTGTTTGUTGGGAAAGGGGUTGATGTTGUAATGAUAGGTTAAAUAGUAAUAGGAUATTGAUTGGUATUTGUAAGUTGAGUTUAGUTUAGAGAGGXGAGGAGUAUAGGGGAGGGAGGAAAATUURGGTGTGGATUTUAUUUAUARGGUUUAUTGGGTGUTUUTGGUAGARGGAATTATGGGTGUTTTTAUTUTUTUATTTTAAAAATGTGUTTTTTATGTGTATTGTAAAAGTAAUAGATTUUUA414TGGGAATUTGTTAUTTTTAUAATAUAUATAAAAAGUAUATTTTTAAAATGAGAGAGTAAAAGUAUUUATAATTURGTUTGUUAGGAGUAUUUAGTGGGURGTGTGGGTGAGATUUAUAURGGGATTTTUUTUUUTUUUUTGTGUTUUTXGUUTUTUTGAGUTGAGUTUAGUTTGUAGATGUUAGTUAATGTUUTGTTGUTGTTTAAUUTGTUATTGUAAUATUAGUUUUTTTUUUAGUAAAUAGGGRGTTGGUAGGTATGUAGGGUUUTUUUTURGGAUAAGTUTGAGGAUUUTGATUTG415UAUTTGGUTUTRGTGGUTGGGAUAGATTGUTTUUTTUUTUTUTUUTGGGTGUUAGGTAGGUUUAGAAAUUAUUTGATGTUAGUAAGGUUTGGUUAUUUAUTGGTGGGGAGGAAGTGGGRGGGTGUUUAGGGAUAGATGAGURGGGUAGAXGTGUUUTGAGGUAGUAUAGTUAGGGUTGARGTGGGUATTATGUAUUTRGGGGUTTTUAGAGUTGGUTURGGTUURGTTTGUUUAUATUAAGUAGGTUAGAGTGGAGAGGGUUAGGGGRGUTGGGGTUAAGGUATGUAUTGAUUAGGRGTU416GARGUUTGGTUAGTGUATGUUTTGAUUUUAGRGUUUUTGGUUUTUTUUAUTUTGAUUTGUTTGATGTGGGUAAARGGGAURGGAGUUAGUTUTGAAAGUUURGAGGTGUATAATGUUUARGTUAGUUUTGAUTGTGUTGUUTUAGGGUAXGTUTGUURGGUTUATUTGTUUUTGGGUAUURGUUUAUTTUUTUUUUAUUAGTGGGTGGUUAGGUUTTGUTGAUATUAGGTGGTTTUTGGGUUTAUUTGGUAUUUAGGAGAGAGGAAGGAAGUAATUTGTUUUAGUUARGAGAGUUAAGTG417ATUUAUAUTTGAAUATAUAGAUATUUTTTTUUAGGGTGTGTTGTGUTRGATAUUTTTAATTUUTGTUTGUATTUUAGGGUUTGUUUAGUUTUTTUUTGGUTUUUUAGUUUAGUUTGGTUUTTURGGUUTUUUTGTUATUUUUAUUTUTXGTGTGTGUAUAAGUAGGGAUUAGGTAGGGAGAURGGUAGATGUTGUTUTUTGTUUUTGGGGTTTUTTTTUTTAGTGTTGUTUUUAUAUUUARGRGATGUTTTAATTAAUTGUUAUAUTUAGGUTTTUTUAGTGGGGAGAGTUAGAAATAGA418UTATTTUTGAUTUTUUUUAUTGAGAAAGUUTGAGTGTGGUAGTTAATTAAAGUATRGRGTGGGTGTGGGAGUAAUAUTAAGAAAAGAAAUUUUAGGGAUAGAGAGUAGUATUTGURGGTUTUUUTAUUTGGTUUUTGUTTGTGUAUAUAXGAGAGGTGGGGATGAUAGGGAGGURGGAAGGAUUAGGUTGGGUTGGGGAGUUAGGAAGAGGUTGGGUAGGUUUTGGAATGUAGAUAGGAATTAAAGGTATRGAGUAUAAUAUAUUUTGGAAAAGGATGTUTGTATGTTUAAGTGTGGATG419TUUUAGUUAUTURGUAGTUAUTUUTGAUUUAGAAAAGAAUAAUUAUAGUTGGGUUUAGUAUUURGGGUUAUTUUUTGUAGUTGUUUAUAUATUTGGUAGUTGGGTUUAUTTATGUAATGTGGATXGGGUTTUTTAUATUTGAAATUTGXGTUTUTATUUUTUUTUTGAGAUUAGTGTUTUUTGUUAGUTTUUATGGUUURGGGATGAUUTUAUTUTUUUAGGGTUTUUUTGRGTUUTGGGAGUTUTGGURGAGGAGUAGUAGGGGUTGATGGUAGAGRGGGGGUAGGTUAGAGUTUAGUA420GUTGAGUTUTGAUUTGUUUURGUTUTGUUATUAGUUUUTGUTGUTUUTRGGUUAGAGUTUUUAGGARGUAGGGAGAUUUTGGGAGAGTGAGGTUATUURGGGGUUATGGAAGUTGGUAGGAGAUAUTGGTUTUAGAGGAGGGATAGAGAXGUAGATTTUAGATGTAAGAAGUUXGATUUAUATTGUATAAGTGGAUUUAGUTGUUAGATGTGTGGGUAGUTGUAGGGAGTGGUURGGGGTGUTGGGUUUAGUTGTGGTTGTTUTTTTUTGGGTUAGGAGTGAUTGRGGAGTGGUTGGGAU421UUAAARGRGGUAUARGGGGARGGUUUUTUURGGGGTUAGGUTUAUTGGUTUUTTUUUTTUAGRGUUAUUAGGUAGGAGGGUUAARGGTUAUAUAGGAGGUAUUUTUAUUTGUUTTTGUAUUAGUAAATAAAGTGUATUUUATTTTXGTGTGAGXGTRGGUURGGTGAGTUAGUUUTTURGGGUUUTTTUUTGTTUTUAGGGUAGGGGGRGTGRGUTGAGUUAGAGGTAGATUTGUAGAAAGGGUUURGAUTGGGUUTRGGGUAGGGURGGRGUUUAUUAUAUTUTGGGGGTUAGUTATGU422GUATAGUTGAUUUUUAGAGTGTGGTGGGRGURGGUUUTGUURGAGGUUUAGTRGGGGUUUTTTUTGUAGATUTAUUTUTGGUTUAGRGUARGUUUUUTGUUUTGAGAAUAGGAAAGGGUURGGAAGGGUTGAUTUAURGGGURGAXGUTUAUAXGAAAATGGGATGUAUTTTATTTGUTGGTGUAAAGGUAGGTGAGGGTGUUTUUTGTGTGAURGTTGGUUUTUUTGUUTGGTGGRGUTGAAGGGAAGGAGUUAGTGAGUUTGAUUURGGGAGGGGURGTUUURGTGTGURGRGTTTGG423GUAGGAAGGGUUUAGARGAUAUUUUUAUAGAUATATGUUAGUUUUTURGGGTGAUUAAAATUATUTUAGTAAAGGUAGATGAGGUUAAGRGAAAAGGGGTGGGTGGAAGAAURGGUTUTGAGTUTUAGUUUAUAGAUAUTRGGAUAUTXGTRGGUURGGTAGGUAGGGGTTUUTGGTGGUUTUAGGUTGTUAGGUURGGUUUUUTUURGUAGUTGTUTUUAGUTUUUAUUTUUUURGUUUAUUUUUUAGGAUTUUTATTTUAUTGAGGAGATTAAGAUUAUUTGGRGAGAAUUUUTUUUA424GGGAGGGGTTUTRGUUAGGTGGTUTTAATUTUUTUAGTGAAATAGGAGTUUTGGGGGGTGGGRGGGGGAGGTGGGAGUTGGAGAUAGUTGRGGGAGGGGGURGGGUUTGAUAGUUTGAGGUUAUUAGGAAUUUUTGUUTAURGGGURGAXGAGTGTURGAGTGTUTGTGGGUTGAGAUTUAGAGURGGTTUTTUUAUUUAUUUUTTTTRGUTTGGUUTUATUTGUUTTTAUTGAGATGATTTTGGTUAUURGGAGGGGUTGGUATATGTUTGTGGGGGTGTRGTUTGGGUUUTTUUTGUT425AGGTGAGATUTGGAGGTTGRGGGGUAGTTAGUAAGTGGGAGAGAGUTGUATGRGGGGAAGGTGGGAGGRGTTGUAGGAAAGGTGAGGGAGAUAUAGUTGAGUTGTGGTGUTGGUUAGUTGGGGUUTTGRGUUTTATURGGGUAUTGTGAXGGUUAUTAAUAGGTTTTAAGTAURGGAATGAUATGATRGGATTTGTAATTTAAUTAGATUUTTUTGAUTGUTGTTGGGGGAAUAGAUTGTUAAUUTUAUAAUAGUAUTGTUAGUTGAGTATTAGAUAAATGATGAAUUTGGGUUUAGGGA426UUUTGGGUUUAGGTTUATUATTTGTUTAATAUTUAGUTGAUAGTGUTGTTGTGAGGTTGAUAGTUTGTTUUUUUAAUAGUAGTUAGAAGGATUTAGTTAAATTAUAAATURGATUATGTUATTURGGTAUTTAAAAUUTGTTAGTGGUXGTUAUAGTGUURGGATAAGGRGUAAGGUUUUAGUTGGUUAGUAUUAUAGUTUAGUTGTGTUTUUUTUAUUTTTUUTGUAARGUUTUUUAUUTTUUURGUATGUAGUTUTUTUUUAUTTGUTAAUTGUUURGUAAUUTUUAGATUTUAUUTG427TGTGTTAUUUUAGAAAGUAAGGARGUTTUUAAAGATGTTUAGAGUAGTGTTUAAAGGGATGUUUAUTGGTUAGTUUUAAURGUTGTGAAUURGGAAAATUTGAGAUTGGTGTUAGTTAATTTAGAAAGTTTATTTTGUUAAGGTTGAGGAXGTATGUUTGTGAUAUAGUUTUAGGAAGTUUTGATGAUATGTGUUUAAGGTGGTTGGGGTGTAGUTTGATTTTATAUAUTTAGGGAGUATGAGAUATUAATTAAGTAUAUTTGAGAAATAUATRGGTTTGGTUTAGAAAGGRGGGAUAAU428GTTGTUURGUUTTTUTAGAUUAAAURGATGTATTTUTUAAGTGTAUTTAATTGATGTUTUATGUTUUUTAAGTGTATAAAATUAAGUTAUAUUUUAAUUAUUTTGGGUAUATGTUATUAGGAUTTUUTGAGGUTGTGTUAUAGGUATAXGTUUTUAAUUTTGGUAAAATAAAUTTTUTAAATTAAUTGAUAUUAGTUTUAGATTTTURGGGTTUAUAGRGGTTGGGAUTGAUUAGTGGGUATUUUTTTGAAUAUTGUTUTGAAUATUTTTGGAAGRGTUUTTGUTTTUTGGGGTAAUAUA429TGAGAATAATGTUTGGTATGRGAGGAGUAUUAGUAAATRGTGUTUATUATTUUAGRGGAGUAAATTGTTGUTGTUTUTUAURGGGUTTTGGGTTAUTGAGGUTGUTATTTATTAAAGTGTGGGTTGTGAUTUATTAUTAGGTUATGAAATXGGTGTAGTGGTAGUAAUUAGUUUTTAAAGAAATGAAURGGGGURGGGRGRGGTGGTTUAUAUUTGTAATUUUAGUAUTTTGGGAGGURGAGGRGGGTGGATUARGAGGTUAAGAGATRGAGAUUATUUTGGUUAAUATGGTGAAAUURG430RGGGTTTUAUUATGTTGGUUAGGATGGTUTRGATUTUTTGAUUTRGTGATUUAUURGUUTRGGUUTUUUAAAGTGUTGGGATTAUAGGTGTGAAUUAURGRGUURGGUUURGGTTUATTTUTTTAAGGGUTGGTTGUTAUUAUTAUAUXGATTTUATGAUUTAGTAATGAGTUAUAAUUUAUAUTTTAATAAATAGUAGUUTUAGTAAUUUAAAGUURGGTGAGAGAUAGUAAUAATTTGUTURGUTGGAATGATGAGUARGATTTGUTGGTGUTUUTRGUATAUUAGAUATTATTUTUA431AGGATGGAGGURGGGGAGGUAGRGURGURGGRGGGGGRGGGRGGURGRGURGUAGGRGGUTGGGGUAAGTGGGTGRGGUTUAARGTGGGGGGUARGGTGTTUUTGAUUAUURGGUAGARGUTGTGURGRGAGUAGAAGTUUTTUUTUAGUXGUUTGTGUUAGGGGGAAGAGUTGUAGTRGGAURGGGTGAGGUUUURGGGGTGGGRGGRGAGRGGGRGGTGGGTUUTURGUTRGUURGARGRGGGGUTGTRGGGUUTGGUTRGUURGUUAGGUTGGGGAUURGGURGGGTTUATTTURGA432TRGGAAATGAAUURGGURGGGTUUUUAGUUTGGRGGGRGAGUUAGGUURGAUAGUUURGRGTRGGGRGAGRGGAGGAUUUAURGUURGUTRGURGUUUAUUURGGGGGUUTUAUURGGTURGAUTGUAGUTUTTUUUUUTGGUAUAGGXGGUTGAGGAAGGAUTTUTGUTRGRGGUAUAGRGTUTGURGGGTGGTUAGGAAUAURGTGUUUUUUARGTTGAGURGUAUUUAUTTGUUUUAGURGUUTGRGGRGRGGURGUURGUUUURGURGGRGGRGUTGUUTUUURGGUUTUUATUUT433TUTAUTGATGRGGAGAURGAGUUUUAGGGUAGUAGAGUUUTAGUTTRGRGUTAUARGGUTGTGGGRGUTGRGUUUUAGGGUARGGURGGUUUAGGTRGTGGUUUAUTRGGGAUURGRGGUTUAURGGTGRGGTTGARGRGGUARGGGAAGXGGTAGGTGUTUAGUAUUTUUTUUTRGTUUTGUTRGTRGATGAUURGGUAUTGGRGUAGATARGGRGTGAGUTTGGURGGGTTUAGGGRGRGAGUUAGURGATGURGGARGUUUTRGATTRGUTUUUAUAGRGRGTUUTUUTURGUUTUA434TGAGGRGGAGGAGGARGRGUTGTGGGAGRGAATRGAGGGRGTURGGUATRGGUTGGUTRGRGUUUTGAAUURGGUUAAGUTUARGURGTATUTGRGUUAGTGURGGGTUATRGARGAGUAGGARGAGGAGGAGGTGUTGAGUAUUTAUXGUTTUURGTGURGRGTUAAURGUAURGGTGAGURGRGGGTUURGAGTGGGUUARGAUUTGGGURGGURGTGUUUTGGGGRGUAGRGUUUAUAGURGTGTAGRGRGAAGUTAGGGUTUTGUTGUUUTGGGGUTRGGTUTURGUATUAGTAGA435UTUAUUTTTUUTAGTTTAGAAAATUUUTUAUTGUTTUUUUAATGGAGGUTGUUUUAGGAGTGGUUUAGTGGGGUUAAUUAGUTGTTUTATGUUAGUAGUTURGGAGTATGTAUATTTUUAUTUTGGTTUAAAUTTGTTUTTUTATTUAXGGUUUUATTAAGAAAAAUATTUATUTGUAGGUTGGAURGGGTTGGGATGUAGUAAGTTGGTGTGGUTAUTURGAGTGTGTGAUAUAUUTGUAGGGGUUTGTGAGUAGTGGGAGGGUUAGAUATGTGGATTUUUAGGGUTGGTGGUTTUUTT436AGGAAGUUAUUAGUUUTGGGAATUUAUATGTUTGGUUUTUUUAUTGUTUAUAGGUUUUTGUAGGTGTGTUAUAUAUTRGGAGTAGUUAUAUUAAUTTGUTGUATUUUAAUURGGTUUAGUUTGUAGATGAATGTTTTTUTTAATGGGGUXGTGAATAGAAGAAUAAGTTTGAAUUAGAGTGGAAATGTAUATAUTURGGAGUTGUTGGUATAGAAUAGUTGGTTGGUUUUAUTGGGUUAUTUUTGGGGUAGUUTUUATTGGGGAAGUAGTGAGGGATTTTUTAAAUTAGGAAAGGTGAGA437AARGUTGAUATUTTTURGGGTGTUTGAAAAUAGAAUTGGUUTTUUTAAGAAUTAAUAARGATAUTGTTTTUAGUUARGTTUUUTTUUTGTTUTTGUTAUARGUTUTGTUAAATAGGTGGUUAGAGGUURGGGTGUAGATGUAGTGGUTUAXGTUAGTAATUUUAGUAUTUTGGGAGGUTGGTGGGRGGATUAUTTGAGGUUAGGAGTTTAAAGAUUAGUTTGGGUAAUATGGTGAAAUUUTGTUTUTAUTAAAAATAUAAAAAATTAGURGGGTGTGGTGGUAUAAAUUTGTAGTTUUAG438UTGGAAUTAUAGGTTTGTGUUAUUAUAUURGGUTAATTTTTTGTATTTTTAGTAGAGAUAGGGTTTUAUUATGTTGUUUAAGUTGGTUTTTAAAUTUUTGGUUTUAAGTGATURGUUUAUUAGUUTUUUAGAGTGUTGGGATTAUTGAXGTGAGUUAUTGUATUTGUAUURGGGUUTUTGGUUAUUTATTTGAUAGAGRGTGTAGUAAGAAUAGGAAGGGAARGTGGUTGAAAAUAGTATRGTTGTTAGTTUTTAGGAAGGUUAGTTUTGTTTTUAGAUAUURGGAAAGATGTUAGRGTT439GAGGUUUAUUUARGUUUUUAGUTUARGATATUTGUAGAGATGUUAAAUUUTGGUAGAGGAAUTUAGGUUATGTGUTTUAGUTGUTUUUTUAUTUUTUUAUTUUUTGUURGGGUUUTGAGUUAGGAGUUAGGUAUAUAGUTGGAUUUATUXGUUAATGUUAUUUAUUUTTGTGUUUAGUAUURGGUUUARGGUAGGTGUTUAGTGTGUAGGUUUAUATGTAUTAGGTGUAAGGUAARGAUAUAUUAUAUAGGAUAAGGATGUAAAGUAUUTTUTGGGUUUTTUTGRGGUTUTGUUTTUUUA440TGGGAAGGUAGAGURGUAGAAGGGUUUAGAAGGTGUTTTGUATUUTTGTUUTGTGTGGTGTGTRGTTGUUTTGUAUUTAGTAUATGTGGGUUTGUAUAUTGAGUAUUTGURGTGGGURGGGTGUTGGGUAUAAGGGTGGGTGGUATTGGXGGATGGGTUUAGUTGTGTGUUTGGUTUUTGGUTUAGGGUURGGGUAGGGAGTGGAGGAGTGAGGGAGUAGUTGAAGUAUATGGUUTGAGTTUUTUTGUUAGGGTTTGGUATUTUTGUAGATATRGTGAGUTGGGGGRGTGGGTGGGUUTU441GGAGGUAAARGGGAAUURGGUTGGRGGGUTGRGAGURGGTAGGGARGUTGGGGTUUAGGGUTGUTGGAUAGUUURGUUUTGTAUUTUTUUUUATUUUTUAUTTAATUUTGGGTURGAAATAGUUURGGGTAATUUUAGGGRGAGGUAGTXGGGAATTAAUUUUAGUUTTGAAGTAAGAGAUAGAGGRGTUUAUAGAAGAGGGUTUTGRGRGTUURGGAUTGGAUAUAGRGUAGAGTUUATTUUAGGGAUAURGUAAUURGUAAGRGAUUUAGGUURGUTUUAGGGRGGGATURGRGRGGU442GURGRGRGGATUURGUUUTGGAGRGGGUUTGGGTRGUTTGRGGGTTGRGGTGTUUUTGGAATGGAUTUTGRGUTGTGTUUAGTURGGGARGRGUAGAGUUUTUTTUTGTGGARGUUTUTGTUTUTTAUTTUAAGGUTGGGGTTAATTUUXGAUTGUUTRGUUUTGGGATTAUURGGGGUTATTTRGGAUUUAGGATTAAGTGAGGGATGGGGAGAGGTAUAGGGRGGGGUTGTUUAGUAGUUUTGGAUUUUAGRGTUUUTAURGGUTRGUAGUURGUUAGURGGGTTUURGTTTGUUTUU443UATGTGUTGAGATGGAGAAGGRGUUAGTGTUAGUAUTAGAUAGGUTGAGATGTUAAGTGGAAATGTUAAGGAGGTGGTGGAGGTGGTGGGAGUTGUAGGGUTGTGAGGUURGGGAGAGGGUUAGAGUTGUAGUTTTAAATTGGAGGGTUAXGGUATGTGGAGGUUAAGGAAGUAGATGGGATGTURGGGGAGAGAGTATGGAUTGAAGUAGUTAAAGAATTGUAGUATUTAATGGAUAGGAAGAGGGGUAGRGAUAGRGATGGAGUUTGAGAAGGAGGGTGUAGTGTUUUUAAGUUATGT444AUATGGUTTGGGGAUAUTGUAUUUTUUTTUTUAGGUTUUATRGUTGTRGUTGUUUUTUTTUUTGTUUATTAGATGUTGUAATTUTTTAGUTGUTTUAGTUUATAUTUTUTUUURGGAUATUUUATUTGUTTUUTTGGUUTUUAUATGUXGTGAUUUTUUAATTTAAAGUTGUAGUTUTGGUUUTUTUURGGGUUTUAUAGUUUTGUAGUTUUUAUUAUUTUUAUUAUUTUUTTGAUATTTUUAUTTGAUATUTUAGUUTGTUTAGTGUTGAUAUTGGRGUUTTUTUUATUTUAGUAUATG445UUUTUAGGTTTGGTTTUTGTTGURGUTGTTGTTTTUTTTTUUAAUATUATAAGUUTUTTUUTTATUTTTUUATGTUTGUAUAUAGGAAGRGGUATUAUTTGTTTTTUATGTUUTGRGUATRGAGGUAUAUTTTUTGUTUUTUTTTGTGUXGUUAGURGGUUUAGGUUUAUAGATGGTAGGAUTTGTGUUUUAGGUTGUTGTGTGAGTUAGAGTUAGGUAGGAAGUAAATGGUAAUTTUAURGRGGTGAUTGAGGAATGUTTAARGAAGGRGURGUUUTTGAUAARGGTGTGGGTTGGTAA446TTAUUAAUUUAUAURGTTGTUAAGGGRGGRGUUTTRGTTAAGUATTUUTUAGTUAURGRGGTGAAGTTGUUATTTGUTTUUTGUUTGAUTUTGAUTUAUAUAGUAGUUTGGGGUAUAAGTUUTAUUATUTGTGGGUUTGGGURGGUTGGXGGUAUAAAGAGGAGUAGAAAGTGTGUUTRGATGRGUAGGAUATGAAAAAUAAGTGATGURGUTTUUTGTGTGUAGAUATGGAAAGATAAGGAAGAGGUTTATGATGTTGGAAAAGAAAAUAAUAGRGGUAAUAGAAAUUAAAUUTGAGGG447TGUTUUTUTTTGTGURGUUAGURGGUUUAGGUUUAUAGATGGTAGGAUTTGTGUUUUAGGUTGUTGTGTGAGTUAGAGTUAGGUAGGAAGUAAATGGUAAUTTUAURGRGGTGAUTGAGGAATGUTTAARGAAGGRGURGUUUTTGAUAAXGGTGTGGGTTGGTAAAAGGAAAUAGURGGGAGUUUTGUAGRGURGGTGURGUUAURGTTTAGTUTGAUTGTGUATTTGAUTAAGTUAUAAGAGGUUAGGUUTGTGAUTTGTURGAGGGAAAAAUUAUUAGAAAAUUAGGTGTUTGGGUT448AGUUUAGAUAUUTGGTTTTUTGGTGGTTTTTUUUTRGGAUAAGTUAUAGGUUTGGUUTUTTGTGAUTTAGTUAAATGUAUAGTUAGAUTAAARGGTGGRGGUAURGGRGUTGUAGGGUTUURGGUTGTTTUUTTTTAUUAAUUUAUAUXGTTGTUAAGGGRGGRGUUTTRGTTAAGUATTUUTUAGTUAURGRGGTGAAGTTGUUATTTGUTTUUTGUUTGAUTUTGAUTUAUAUAGUAGUUTGGGGUAUAAGTUUTAUUATUTGTGGGUUTGGGURGGUTGGRGGUAUAAAGAGGAGUA449UTGTGUTUAAGAGUUAUTTUTTAAURGGGGTGGGAGGAAGUAGUTTUAGGAAUTGUTGAGAGAGUAGAAUTUARGUTUUAGGGUTUAGAGUAGGAGGTAGGGTGTGRGGUAAGRGUTGGUURGGAUAGAAGUAGAGTGGGUUUTGGTUTXGGGUAGGATGTTTUTGAUTUAUATTTUUTGAGGAGAGAAAGUTAAGUTUTTTGUUTAATGTUTUTGTUTUUUUTTUUAGAAAAATGUUTUAGUTUTTURGGUUTGAAGGAATGGUUTUUTUURGGGUUUUATGATTUTTTUUTGTGTGGG450UUUAUAUAGGAAAGAATUATGGGGUURGGGAGGAGGUUATTUUTTUAGGURGGAAGAGUTGAGGUATTTTTUTGGAAGGGGAGAUAGAGAUATTAGGUAAAGAGUTTAGUTTTUTUTUUTUAGGAAATGTGAGTUAGAAAUATUUTGUUXGAGAUUAGGGUUUAUTUTGUTTUTGTURGGGUUAGRGUTTGURGUAUAUUUTAUUTUUTGUTUTGAGUUUTGGAGRGTGAGTTUTGUTUTUTUAGUAGTTUUTGAAGUTGUTTUUTUUUAUUURGGTTAAGAAGTGGUTUTTGAGUAUAG451TTTTTTTTTTGAGAUAGAGTUTRGUTUTGTUAUUUAGGUTGGAGTGUAGTGGRGTGATUTRGGUTUAUTGUAAGUTUUAUUTUURGGGTTUATGUUATTUTUUTGUUTUAGUTTUUTGAGTATUTGGGAUTAUAGGUAUTUAUUAUUAXGUURGGUTAATTTTTTTTTTTTATTTTTAGTGGAGARGGGGTTTUAUTGTGTTAGUUAGGATGGTUTRGATUTUUTGAUUTRGTGATUAGUURGUUTUAGUUTUUUAAAGTGUTGGGATTAUAGGTGTGAGUUAUUTUAUURGGUUTGUTA452AGUAGGURGGGTGAGGTGGUTUAUAUUTGTAATUUUAGUAUTTTGGGAGGUTGAGGRGGGUTGATUARGAGGTUAGGAGATRGAGAUUATUUTGGUTAAUAUAGTGAAAUUURGTUTUUAUTAAAAATAAAAAAAAAAAATTAGURGGGXGTGGTGGTGAGTGUUTGTAGTUUUAGATAUTUAGGAAGUTGAGGUAGGAGAATGGUATGAAUURGGGAGGTGGAGUTTGUAGTGAGURGAGATUARGUUAUTGUAUTUUAGUUTGGGTGAUAGAGRGAGAUTUTGTUTUAAAAAAAAAAU453TTGUUTUTTTTGATTTTTTTUTTTGGGUAGGAGTTAGAATGUAAAATAUAGATTUTATUTGTATAAAGUAUAUAAGAGATGUTTGGGATUTGGTGATGUTGUAURGGAGATTTUAAUUTGTTTTTUAAAGTGATTUUTAGGGAGTGTGAXGATUTUAAUTUTTTTGGAAGTGAUTTGTUAAAUUATGAGUUATGUTGAGTTUAGUAUAAGTAATATGAGGRGAGGUAAGGUAAGTGGGTGAGTAAGGAGGAAGUAGUUUAGATGAGURGGUAGAGTGUUUAUTGGGAGTGAGGUATGATG454ATUATGUUTUAUTUUUAGTGGGUAUTUTGURGGUTUATUTGGGUTGUTTUUTUUTTAUTUAUUUAUTTGUUTTGUUTRGUUTUATATTAUTTGTGUTGAAUTUAGUATGGUTUATGGTTTGAUAAGTUAUTTUUAAAAGAGTTGAGATXGTUAUAUTUUUTAGGAATUAUTTTGAAAAAUAGGTTGAAATUTURGGTGUAGUATUAUUAGATUUUAAGUATUTUTTGTGTGUTTTATAUAGATAGAATUTGTATTTTGUATTUTAAUTUUTGUUUAAAGAAAAAAATUAAAAGAGGUAAU455AUAAGAGATGUTTGGGATUTGGTGATGUTGUAURGGAGATTTUAAUUTGTTTTTUAAAGTGATTUUTAGGGAGTGTGARGATUTUAAUTUTTTTGGAAGTGAUTTGTUAAAUUATGAGUUATGUTGAGTTUAGUAUAAGTAATATGAGGXGAGGUAAGGUAAGTGGGTGAGTAAGGAGGAAGUAGUUUAGATGAGURGGUAGAGTGUUUAUTGGGAGTGAGGUATGATGAGGATTAUTRGTRGTGGGAGGUATGAGGGUAUTUTUTGGUAAGGTTUUTTGUATUAUUAAAATGAGGTUAU456TGAUUTUATTTTGGTGATGUAAGGAAUUTTGUUAGAGAGTGUUUTUATGUUTUUUARGARGAGTAATUUTUATUATGUUTUAUTUUUAGTGGGUAUTUTGURGGUTUATUTGGGUTGUTTUUTUUTTAUTUAUUUAUTTGUUTTGUUTXGUUTUATATTAUTTGTGUTGAAUTUAGUATGGUTUATGGTTTGAUAAGTUAUTTUUAAAAGAGTTGAGATRGTUAUAUTUUUTAGGAATUAUTTTGAAAAAUAGGTTGAAATUTURGGTGUAGUATUAUUAGATUUUAAGUATUTUTTGTG457AGUAAAUAGAGGGTATGGTUUAAUTTGUUTATGAAURGGGAAGUATAATATTTTAATATTTGTGUUTTAAGUAGTTGTTTTAUTTAAAAGUAUAGGAAATUUTGTUTTTTTTUTTGTTATAAAATUTTAUAAAGUTAUTGGAAAGATUTUXGUAGGUUAGTGGTTTTUAAAGTGGGTTUUUAGAAUTAGUAAUAGUTGAATUATURGGGAAUTGGTTAGAAATGUAAAGTUTRGURGUUAUUUUTUAAUUUUUUAGAUUTAATGAAUUAGAAATTUTGGGGTGTGGUUUAGTGGUUTGRG458RGUAGGUUAUTGGGUUAUAUUUUAGAATTTUTGGTTUATTAGGTUTGGGGGGTTGAGGGGTGGRGGRGAGAUTTTGUATTTUTAAUUAGTTUURGGATGATTUAGUTGTTGUTAGTTUTGGGAAUUUAUTTTGAAAAUUAUTGGUUTGXGGAGATUTTTUUAGTAGUTTTGTAAGATTTTATAAUAAGAAAAAAGAUAGGATTTUUTGTGUTTTTAAGTAAAAUAAUTGUTTAAGGUAUAAATATTAAAATATTATGUTTUURGGTTUATAGGUAAGTTGGAUUATAUUUTUTGTTTGUT459GUUUTAUUURGUTUTUUURGAUTUUUURGGGUURGGUUTGRGUUTTUUTGRGGTGURGAGGAGRGGTGGRGUUUTGGGTGAAGAAGTUURGURGAGTRGAGGGGRGUAATGGAGGAGRGURGGAAUAGGTUTUTUATTURGAGTAGUTAUXGTTGUAUTGTGRGAGTGTAAAAGTUAUTTUUAUURGGTUTUAGTTGTTUUAAUUTUAGTTGAAGTGAGGAGGTTGGAUTGGAAGGTTTUTGGGGTUAUTUUAGTGAGGUTGGGGTTUTAGTUUUAATUTUAURGTGGUAUUUUAAAGGU460GUUTTTGGGGTGUUARGGTGAGATTGGGAUTAGAAUUUUAGUUTUAUTGGAGTGAUUUUAGAAAUUTTUUAGTUUAAUUTUUTUAUTTUAAUTGAGGTTGGAAUAAUTGAGAURGGGTGGAAGTGAUTTTTAUAUTRGUAUAGTGUAAXGGTAGUTAUTRGGAATGAGAGAUUTGTTURGGRGUTUUTUUATTGRGUUUUTRGAUTRGGRGGGAUTTUTTUAUUUAGGGRGUUAURGUTUUTRGGUAURGUAGGAAGGRGUAGGURGGGUURGGGGGAGTRGGGGAGAGRGGGGTAGGGU461GGAUAUAATUTUTGTTUTTUAAAGTTGGUAUTAAGAGUTUUTUUTGRGGTTUUUUTTUUTUTUUTRGAGUAGUAAAGGRGTGGTUUAUAATGUUUAUUUTGTGGGGTUTAGGGGTGUURGGUTTGUTGAUUTUUAGGUUUUUTUTGTGGXGAGGTTTGGAUTGUATAUATGGTGUAGGUUUUTUATUAUTGGAGUTGUUAGGAUAGUAUTGGAGAUUUTAAGUUAATAUUTATTTTTGGUAATAATTATUAAGUATTTGTAAAAGUURGGGTATGUTGGUAAATUTTTTTAAAATAAGAG462UTUTTATTTTAAAAAGATTTGUUAGUATAUURGGGUTTTTAUAAATGUTTGATAATTATTGUUAAAAATAGGTATTGGUTTAGGGTUTUUAGTGUTGTUUTGGUAGUTUUAGTGATGAGGGGUUTGUAUUATGTATGUAGTUUAAAUUTXGUUAUAGAGGGGGUUTGGAGGTUAGUAAGURGGGUAUUUUTAGAUUUUAUAGGGTGGGUATTGTGGAUUARGUUTTTGUTGUTRGAGGAGAGGAAGGGGAAURGUAGGAGGAGUTUTTAGTGUUAAUTTTGAAGAAUAGAGATTGTGTUU463AUTTGAGRGUTTUTUUAUUUUAGUAGGUURGUTGUUATUAAGGGUTTAUUUTGTGGGUTGUUUARGUTGUTGTAAUUAGTGAUUAUAAGUTURGTGGTGTTGAGAAGUAUATGTTTUTUUTUUUARGGUTGTGTAGGTURGGAGTUUTAXGGGUTUAGUUAGTUUUUUTGUTUUAGGTTTAAUUAGGURGGAATUAAGATGUUAGGGUUTGGUTGTGUTTTGGAGGUTUTTGGTGAGAAUUTGUTTUTGGUUTGGTGUAGGGTGTGGUAGAATUURGATGUTTGAGTTTGAATGGTGAAA464TTTUAUUATTUAAAUTUAAGUATRGGGATTUTGUUAUAUUUTGUAUUAGGUUAGAAGUAGGTTUTUAUUAAGAGUUTUUAAAGUAUAGUUAGGUUUTGGUATUTTGATTURGGUUTGGTTAAAUUTGGAGUAGGGGGAUTGGUTGAGUUXGTAGGAUTURGGAUUTAUAUAGURGTGGGAGGAGAAAUATGTGUTTUTUAAUAUUARGGAGUTTGTGGTUAUTGGTTAUAGUAGRGTGGGUAGUUUAUAGGGTAAGUUUTTGATGGUAGRGGGUUTGUTGGGGTGGAGAAGRGUTUAAGT465AAAUTUARGUTGGUUUAAGAGGAGGAAUAGAGAAGUTTUUTGGUTGAGGUUUAGURGAUTGUTGAUURGGAAAAGTTTUTRGAGGTGAUTUAUATUUUUAGUUTUTGUAUATGTGGGTGAGUUAGTTGTAGUTUTGTTUUXGTGAUTGAGUAXGGGAXGURGGAGGTATTUATUAGGUATGAGGTTATUTGUUTAUTTUUUATGTGTUAGURGAGTGAURGAATUTUAGTUUUTTAGUUUUTAUATUUUTAGGGTUUTAGTGGAUTGTAAGUTGGTGATAAGAGTTGTGUTGUUUTUAUT466GTGAGGGUAGUAUAAUTUTTATUAUUAGUTTAUAGTUUAUTAGGAUUUTAGGGATGTAGGGGUTAAGGGAUTGAGATTRGGTUAUTRGGUTGAUAUATGGGAAGTAGGUAGATAAUUTUATGUUTGATGAATAUUTURGGXGTUUXGTGUTUAGTUAXGGGAAUAGAGUTAUAAUTGGUTUAUUUAUATGTGUAGAGGUTGGGGATGTGAGTUAUUTRGAGAAAUTTTTURGGGTUAGUAGTRGGUTGGGUUTUAGUUAGGAAGUTTUTUTGTTUUTUUTUTTGGGUUAGRGTGAGTTTT467AUTTGAGRGUTTUTUUAUUUUAGUAGGUURGUTGUUATUAAGGGUTTAUUUTGTGGGUTGUUUARGUTGUTGTAAUUAGTGAUUAUAAGUTURGTGGTGTTGAGAAGUAUATGTTTUTUUTUUUARGGUTGTGTAGGTURGGAGTUUTAXGGGUTUAGUUAGTUUUUUTGUTUUAGGTTTAAUUAGGURGGAATUAAGATGUUAGGGUUTGGUTGTGUTTTGGAGGUTUTTGGTGAGAAUUTGUTTUTGGUUTGGTGUAGGGTGTGGUAGAATUURGATGUTTGAGTTTGAATGGTGAAA468TTTUAUUATTUAAAUTUAAGUATRGGGATTUTGUUAUAUUUTGUAUUAGGUUAGAAGUAGGTTUTUAUUAAGAGUUTUUAAAGUAUAGUUAGGUUUTGGUATUTTGATTURGGUUTGGTTAAAUUTGGAGUAGGGGGAUTGGUTGAGUUXGTAGGAUTURGGAUUTAUAUAGURGTGGGAGGAGAAAUATGTGUTTUTUAAUAUUARGGAGUTTGTGGTUAUTGGTTAUAGUAGRGTGGGUAGUUUAUAGGGTAAGUUUTTGATGGUAGRGGGUUTGUTGGGGTGGAGAAGRGUTUAAGT469GRGAATAAAAAGUUAGTGTGTGAGUAAGTUTGTGGGAAGATGUATGUAGAGTGTGAUAGAGAGTTTAGGGGUTRGTGTGAUAATURGTGGAAATGTTTUTAAAGGRGAGGGTATGTGTGTGGGTGTGAGGAUURGGUTGTTGGATGTTTAXGTATTTTATTAGUTAGATARGGGAGUTAATAUTUAATTGUAGTGUAUTAAAUATTATTAGGTGGGTATGATTTTGAGGGAATGAGGGAAGGGAGAUAAGGTUTGGTGAGATUATUTGTGGGATTATUTGTGTGTATTTGUTGGTTTGTA470TAUAAAUUAGUAAATAUAUAUAGATAATUUUAUAGATGATUTUAUUAGAUUTTGTUTUUUTTUUUTUATTUUUTUAAAATUATAUUUAUUTAATAATGTTTAGTGUAUTGUAATTGAGTATTAGUTUURGTATUTAGUTAATAAAATAXGTAAAUATUUAAUAGURGGGTUUTUAUAUUUAUAUAUATAUUUTRGUUTTTAGAAAUATTTUUARGGATTGTUAUARGAGUUUUTAAAUTUTUTGTUAUAUTUTGUATGUATUTTUUUAUAGAUTTGUTUAUAUAUTGGUTTTTTATTRGU471UAGTGAGUTGAGAGUARGUUAUTGUAUTUUAGUUTGGGGGATAGAGTGAGAUTUTGTUTUAAAAAAAGAAAAAAAGAAUTGATUUUAAATGTGTGGGGAGAUTGATTTUAGTAATAATAAAAUTURGGTUTUUUAUAUAGUUAGUTUTGXGTGAATUUUTUTTTUUUTATTGRGATTUUUUTGATTTGAGTGAUAGTAAAAUTURGGTUTUUTGUAUAGUUAGUTUTGRGTGAGTUATTUTTTUTUUUUTGTAATTUUUUTGTUTTGATUUATUAGUTUTGTUTGGGUAGUAGGUAAGGT472AUUTTGUUTGUTGUUUAGAUAGAGUTGATGGATUAAGAUAGGGGAATTAUAGGGGAGAAAGAATGAUTUARGUAGAGUTGGUTGTGUAGGAGAURGGAGTTTTAUTGTUAUTUAAATUAGGGGAATRGUAATAGGGAAAGAGGGATTUAXGUAGAGUTGGUTGTGTGGGAGAURGGAGTTTTATTATTAUTGAAATUAGTUTUUUUAUAUATTTGGGATUAGTTUTTTTTTTUTTTTTTTGAGAUAGAGTUTUAUTUTATUUUUUAGGUTGGAGTGUAGTGGRGTGUTUTUAGUTUAUTG473GGATGTRGGTGTGUUAAUUUUAGUTUUAUUUUAUTGUTAAAGUTTAAGUTUTUUUUTUUUURGTTAAGUTGTATGAUUTTGAGTTUTTTGTGUUTUAUTGTUUTUATUTGTUAAGTGAAAATGUTUUUAGTUUUUAUUTURGGGAGTTGXGTGGGAGGUAUAUATGAAUAUUAGGAAAGTGAGTTTATGUAGUURGGGUUAGGGAUTURGGTUTUTGUUTUTGUUUTAATUUUUARGGUUTGGGGGAARGTGUAGGGUTGAGGAAGRGUAGUUTUTUUTTGGAATUTUAGRGGAAGUTUU474GGAGUTTURGUTGAGATTUUAAGGAGAGGUTGRGUTTUUTUAGUUUTGUARGTTUUUUUAGGURGTGGGGATTAGGGUAGAGGUAGAGAURGGAGTUUUTGGUURGGGUTGUATAAAUTUAUTTTUUTGGTGTTUATGTGTGUUTUUUAXGUAAUTUURGGAGGTGGGGAUTGGGAGUATTTTUAUTTGAUAGATGAGGAUAGTGAGGUAUAAAGAAUTUAAGGTUATAUAGUTTAARGGGGGAGGGGAGAGUTTAAGUTTTAGUAGTGGGGTGGAGUTGGGGTTGGUAUAURGAUATUU475TAATTGAATUAUATAATTUATTTUUATTATUTGAGTTUURGGUTTAGGUTUTTTGAGTAUUARGAATUAGGAATGAUTATGUTUUAUTTUAUUUTTRGUTAGTUAAAGAUTGUUAGGAGGUURGGGGTTGTGGTATTUAARGTTAUAGAXGTAAGGUUUTUUTGUUUAUUUAGUAUTUUAAATATTTUATGAUATATGAAGGUTUTGAUATTGUAAAURGGAUTARGAUAAGUUTTTGAUTTUTURGGGTTGTGAGGAGTTTTAGAAAATAAUTGAGAAGUAAUTTTTTTGAGGATGATG476UATUATUUTUAAAAAAGTTGUTTUTUAGTTATTTTUTAAAAUTUUTUAUAAUURGGAGAAGTUAAAGGUTTGTRGTAGTURGGTTTGUAATGTUAGAGUUTTUATATGTUATGAAATATTTGGAGTGUTGGGTGGGUAGGAGGGUUTTAXGTUTGTAARGTTGAATAUUAUAAUUURGGGUUTUUTGGUAGTUTTTGAUTAGRGAAGGGTGAAGTGGAGUATAGTUATTUUTGATTRGTGGTAUTUAAAGAGUUTAAGURGGGAAUTUAGATAATGGAAATGAATTATGTGATTUAATTA477UAAUATTUUTTGTATUUAGUATUUTTTGUUATGTUATTUTATAGATGUTUTUAUTAAAGTGATGGUUAATTTUUTTAUUUTTRGAATURGGGUTTTGGUAAATGGGATGTTAAUAAUAGUTUUUAAAUAGAGGATUAUATAGTAUTTGXGTGAGUUUAUTUUUUTUTTATGTTUTTUAAGUATGUUATGAGAAUAXGUUTGGGTUAGUUTGUTGAAGGAGUTGAGUTGAGTUATUURGGTGAUAGUUAGUTGAUTUTTAGUAGTGAGAGGUAUUUUUAUAAAGUTGUTUTGUTGAUUAUU478GTGGTUAGUAGAGUAGUTTTGTGGGGGTGUUTUTUAUTGUTAAGAGTUAGUTGGUTGTUAURGGGATGAUTUAGUTUAGUTUUTTUAGUAGGUTGAUUUAGGXGTGTTUTUATGGUATGUTTGAAGAAUATAAGAGGGGAGTGGGUTUAXGUAAGTAUTATGTGATUUTUTGTTTGGGAGUTGTTGTTAAUATUUUATTTGUUAAAGUURGGATTRGAAGGGTAAGGAAATTGGUUATUAUTTTAGTGAGAGUATUTATAGAATGAUATGGUAAAGGATGUTGGATAUAAGGAATGTTGU479GUTUTUAUTAAAGTGATGGUUAATTTUUTTAUUUTTRGAATURGGGUTTTGGUAAATGGGATGTTAAUAAUAGUTUUUAAAUAGAGGATUAUATAGTAUTTGXGTGAGUUUAUTUUUUTUTTATGTTUTTUAAGUATGUUATGAGAAUAXGUUTGGGTUAGUUTGUTGAAGGAGUTGAGUTGAGTUATUURGGTGAUAGUUAGUTGAUTUTTAGUAGTGAGAGGUAUUUUUAUAAAGUTGUTUTGUTGAUUAUUUUAGAUAUARGAGUAAAAGAAATGTTTAUUATTAUATGTUAUTGAG480TUAGTGAUATGTAATGGTAAAUATTTUTTTTGUTRGTGTGTUTGGGGTGGTUAGUAGAGUAGUTTTGTGGGGGTGUUTUTUAUTGUTAAGAGTUAGUTGGUTGTUAURGGGATGAUTUAGUTUAGUTUUTTUAGUAGGUTGAUUUAGGXGTGTTUTUATGGUATGUTTGAAGAAUATAAGAGGGGAGTGGGUTUAXGUAAGTAUTATGTGATUUTUTGTTTGGGAGUTGTTGTTAAUATUUUATTTGUUAAAGUURGGATTRGAAGGGTAAGGAAATTGGUUATUAUTTTAGTGAGAGUA481UUUUAGUUAAAUUAUTRGAUTGUUUUUUATUAUUTATAUTGGURGUTTTTUUUTGGAGUUTGUAUUUAAUAGTGGUAAUAUUTTGTGGUURGAGUUUUTUTTUAGUTTGGTUAGTGGUUTAGTGAGUATGAUUAAUUUAURGGUUTUUTXGTUUTUAGUAUUATUTUUAGRGGUUTUUTURGUUTURGUUTUUUAGAGUUUAUUUUTGAGUTGRGUAGTGUUATUUAARGAUAGUAGTUUUATTTAUTUAGRGGUAUUUAUUTTUUUUARGURGAAUAUTGAUATTTTUUUTGAGUUAUA482TGTGGUTUAGGGAAAATGTUAGTGTTRGGRGTGGGGAAGGTGGGTGURGUTGAGTAAATGGGAUTGUTGTRGTTGGATGGUAUTGRGUAGUTUAGGGGTGGGUTUTGGGAGGRGGAGGRGGAGGAGGURGUTGGAGATGGTGUTGAGGAXGAGGAGGURGGTGGGTTGGTUATGUTUAUTAGGUUAUTGAUUAAGUTGAAGAGGGGUTRGGGUUAUAAGGTGTTGUUAUTGTTGGGTGUAGGUTUUAGGGAAAAGRGGUUAGTATAGGTGATGGGGGGUAGTRGAGTGGTTTGGUTGGGG483GUAGTGGUTGGGUUUUUAUUUUUUAGGAAAUTUAAAAUUUTGGGUUAGURGRGGGTGGRGGGTTGGGGUAGGUAUAAAGAGGGUUTUTGTGRGGURGGUTGGGUTGUUUAUAGGATTUTGGGGGAGGAGGURGGAGURGGTTTUXGTUURGTTUTGUTTUUTGRGGAGGUTGRGGAATGUURGGAGUTUTGGUUUAGUUTGUUURGTUTGGUUUAUURGUAGUUUUTTUUUUATUTTTTUUAGGGUUTTGGGGTAUAGUTGUAGAUTTUTUTGUAAUAGGGUUUTGAGAGUUAUUUTUUA484TGGAGGGTGGUTUTUAGGGUUUTGTTGUAGAGAAGTUTGUAGUTGTAUUUUAAGGUUUTGGAAAAGATGGGGAAGGGGUTGRGGGTGGGUUAGARGGGGUAGGUTGGGUUAGAGUTURGGGUATTURGUAGUUTURGUAGGAAGUAGAAXGGGARGGAAAURGGUTURGGUUTUUTUUUUUAGAATUUTGTGGGUAGUUUAGURGGURGUAUAGAGGUUUTUTTTGTGUUTGUUUUAAUURGUUAUURGRGGUTGGUUUAGGGTTTTGAGTTTUUTGGGGGGTGGGGGUUUAGUUAUTGU485AGGUAUURGTUAUAARGUURGGUTAATTTTTTTGTATTTTTTAGTAGAGARGGGGTTTUAURGTGTTAGUUAGGATGGTUTUAGTUTUUTGAUUTTGTGATUUAUUUAUUTUAGUUTUUUAAAGTGUTGGGATTAUAGATGTGAGUTAUXGUAUURGGUUAAGTTUATGATUTTTUTGTAUTUTGAGUUAGTGTTAUTGGUAAAGAATGUUUTGGGUATTGTGGTGTGGATGGAAGUUAGGUAUATTGUATUUATTUUTTUUTAGAUTAAGTTGUUTGGUUTGTGGAUUTTUTUAGUUAG486UTGGUTGAGAAGGTUUAUAGGUUAGGUAAUTTAGTUTAGGAAGGAATGGATGUAATGTGUUTGGUTTUUATUUAUAUUAUAATGUUUAGGGUATTUTTTGUUAGTAAUAUTGGUTUAGAGTAUAGAAAGATUATGAAUTTGGURGGGTGXGGTAGUTUAUATUTGTAATUUUAGUAUTTTGGGAGGUTGAGGTGGGTGGATUAUAAGGTUAGGAGAUTGAGAUUATUUTGGUTAAUARGGTGAAAUUURGTUTUTAUTAAAAAATAUAAAAAAATTAGURGGGRGTTGTGARGGGTGUUT487TTURGTGGGGATGUAAUUTRGTTTGUUUUTUTGAUTTUUUUATGAGATUTUTRGUTTUUTUUUAUAUUTUUTTTATUUUUUAAUUUUUTGURGGTUUAUUAGGUTGUAGUTGRGGGTUTGRGGGTAGGGGAUATTUUTAGGTUTTGAUXGUUAGAGUAUURGGTUUAGTUURGGUUAUAGUUTTTGGUUUAAGTGAGGGUTGGUUTGGGGAUAAGURGAAATUAGGGUUUTGGUTGTATUUAGAAAGAGAAUTGAGAUURGTTGUUTUUUAUTGGGUUAUUUUURGAUUUUAAUUAUATA488ATGTGGTTGGGGTRGGGGGGTGGUUUAGTGGGAGGUAARGGGTUTUAGTTUTUTTTUTGGATAUAGUUAGGGUUUTGATTTRGGUTTGTUUUUAGGUUAGUUUTUAUTTGGGUUAAAGGUTGTGGURGGGAUTGGAURGGGTGUTUTGGXGGTUAAGAUUTAGGAATGTUUUUTAUURGUAGAUURGUAGUTGUAGUUTGGTGGAURGGUAGGGGGTTGGGGGATAAAGGAGGTGTGGGAGGAAGRGAGAGATUTUATGGGGAAGTUAGAGGGGUAAARGAGGTTGUATUUUUARGGAAT489UTTATAUURGGTUUTRGUUUUTUUAGRGURGGUUTRGUURGRGUTUUTGAGAAAGUUUTGUURGUTURGUTUARGGURGTGUUUTGGUUAAUTTUUTGUTGRGGURGGRGGGUUUTGGGAAGUURGTGUUUUUTTUUUTGUURGGGUUTXGAGGAUTTUUTUTTGGUAGGRGUTGGGGUUUTUTGAGAGUAGGUAGGUURGGUUTTTGTUTURGRGAGGUUUAUUURGGUURGUAUUTTRGUTTTGRGGTUTGAUUUUARGRGUUUUUUTGUAGGGUTGGGUURGGGTGAGGGGAGUTTU490GAAGUTUUUUTUAUURGGGUUUAGUUUTGUAGGGGGGRGRGTGGGGTUAGAURGUAAAGRGAAGGTGRGGGURGGGGTGGGUUTRGRGGAGAUAAAGGURGGGUUTGUUTGUTUTUAGAGGGUUUUAGRGUUTGUUAAGAGGAAGTUUTXGAGGUURGGGUAGGGAAGGGGGUARGGGUTTUUUAGGGUURGURGGURGUAGUAGGAAGTTGGUUAGGGUARGGURGTGAGRGGAGRGGGUAGGGUTTTUTUAGGAGRGRGGGRGAGGURGGRGUTGGAGGGGRGAGGAURGGGTATAAG491AGUTUUTTTATUAGAAAGGGUAGURGUAGAGUURGRGTGTGRGRGATGTGGUTGRGGGTGGGGAGRGGGRGGRGGGUURGGGAUAURGRGGUUAUTGTTUTAGUUURGUUTGGGURGUUTGAURGRGGUTURGUTGRGURGUAGUUURGXGUUUUTUTGGUTUUTGTTUURGGGRGRGGGGAGAAGGRGGRGGGGRGRGUUTGGGUURGRGRGGGTGRGAARGRGAGGTUTTTUUTGGGTGUTUUUAGGTRGGAGGATTUUUAGGGRGGGGGUUATUAGGGTGGRGAGGAAURGGUAGGG492UUUTGURGGTTUUTRGUUAUUUTGATGGUUUURGUUUTGGGAATUUTURGAUUTGGGAGUAUUUAGGAAAGAUUTRGRGTTRGUAUURGRGRGGGUUUAGGRGRGUUURGURGUUTTUTUUURGRGUURGGGAAUAGGAGUUAGAGGGGXGRGGGGUTGRGGRGUAGRGGAGURGRGGTUAGGRGGUUUAGGRGGGGUTAGAAUAGTGGURGRGGTGTUURGGGUURGURGUURGUTUUUUAUURGUAGUUAUATRGRGUAUARGRGGGUTUTGRGGUTGUUUTTTUTGATAAAGGAGUT493TGGAAAAGUUAAUTGTGUAAAUATTRGUTTUTAURGTUAUAAGGTGAAAAGGAAAAATGUUAAAAAGGAGAGUTTGGAAAUAUAGUAGAAGAGUAATGAUUUUUTGUAGAGAAUATGAAATAAGATURGGUAGTGAUUUUAUTAAAGAUAXGGAAAATAAGGTUUAAUUUAGAAUTGGTUAGAGAAUAUUAUTGTGUTTTAGAGTAAUAATTAUAAAGGAAAAGAGGGATRGGGUAUTGTAATATUURGGGAUTGUAGUTTGTAUTUTUTGGGTGGTGUATTUTGTAATTUAATTAAATU494GATTTAATTGAATTAUAGAATGUAUUAUUUAGAGAGTAUAAGUTGUAGTUURGGGATATTAUAGTGUURGATUUUTUTTTTUUTTTGTAATTGTTAUTUTAAAGUAUAGTGGTGTTUTUTGAUUAGTTUTGGGTTGGAUUTTATTTTUXGTGTUTTTAGTGGGGTUAUTGURGGATUTTATTTUATGTTUTUTGUAGGGGGTUATTGUTUTTUTGUTGTGTTTUUAAGUTUTUUTTTTTGGUATTTTTUUTTTTUAUUTTGTGARGGTAGAAGRGAATGTTTGUAUAGTTGGUTTTTUUA495UTGUAGATTGAUAUTGTTAATUAUAAAUAAGUUUAGGGTTGTGTTUAGAGAUAAAGTUAGTGTGAURGGTGAUTGTTAUAGUAATAUAAAATAATGGUAGUAGTUUUAUTAGURGAGGUUAGUATRGAATAGGGUAAGTTAUTUAAAUAXGTUAUUUTAGRGAUUAUTUUAAAUAUUTGTGUTTAAAUTAAUTTAGGGAGUURGGTTTTGUAGGATGTGUAAUUARGTTGTGUUUUUTAGGGUTUAUUAGAUTTTAGTAUUTAATGUAGUTAUUUTUAURGTGGUUUAGGTTUUUAGGGA496UUUTGGGAAUUTGGGUUARGGTGAGGGTAGUTGUATTAGGTAUTAAAGTUTGGTGAGUUUTAGGGGGUAUAARGTGGTTGUAUATUUTGUAAAAURGGGUTUUUTAAGTTAGTTTAAGUAUAGGTGTTTGGAGTGGTRGUTAGGGTGAXGTGTTTGAGTAAUTTGUUUTATTRGATGUTGGUUTRGGUTAGTGGGAUTGUTGUUATTATTTTGTATTGUTGTAAUAGTUAURGGTUAUAUTGAUTTTGTUTUTGAAUAUAAUUUTGGGUTTGTTTGTGATTAAUAGTGTUAATUTGUAGG497AAAUAUAGUUAGTUTGTTUTAGUUTUTGTUUTUATTTTUTTUUUUUTTUUUTTTGUTUUAGTTUUTTGTUUUAUAGTGATGGGUTTGGGAUTATGGGGTGTUUATTURGGGUTTUUUTGGUTTGUTTAUTTTUTUATGGGTGUTTTGAGXGUUTTTTTTGAGURGGUTUAGGUTTTUUUUUUAUAUUUTTTUUTUUUTGUTTUTATUTGGUAGTGAGGGTUAGAGUTTRGGTUAGTGAGTUATUUAAAUUTGGGTGTGGAAAGUAUUTGGGAUAUUAUTTGTATTTGGUTUUTTTTAGUT498AGUTAAAAGGAGUUAAATAUAAGTGGTGTUUUAGGTGUTTTUUAUAUUUAGGTTTGGATGAUTUAUTGAURGAAGUTUTGAUUUTUAUTGUUAGATAGAAGUAGGGAGGAAAGGGTGTGGGGGGAAAGUUTGAGURGGUTUAAAAAAGGXGUTUAAAGUAUUUATGAGAAAGTAAGUAAGUUAGGGAAGUURGGAATGGAUAUUUUATAGTUUUAAGUUUATUAUTGTGGGAUAAGGAAUTGGAGUAAAGGGAAGGGGGAAGAAAATGAGGAUAGAGGUTAGAAUAGAUTGGUTGTGTTT499GTUUUUAAAGGUTGAAUUTTTGATUAATGUAGUUUAAGUTGUARGGGUAGAGAAAGGGTGRGGGGTAGGGGURGGGGTTGGGRGUTGAGUTUUTUTGAAURGGTTGUUAGGUAAUAGAATGGAAATTUARGGGRGGUTAAATGGAGUTUXGUUAUAAATGTTUTGTGGUAAAUURGGAUUUAGTUAUATRGUUUTTTUTUUUUUUTUUUAUUUUAUTGAGTTTTUTUATUTGTAAATGAGAAGGGTGUAGAGAAGAUTUTTTTUTTRGGAGTUAGTGUUTURGGTTTGUAUTGUTTTTUA500TGAAAAGUAGTGUAAAURGGAGGUAUTGAUTURGAAGAAAAGAGTUTTUTUTGUAUUUTTUTUATTTAUAGATGAGAAAAUTUAGTGGGGTGGGAGGGGGGAGAAAGGGRGATGTGAUTGGGTURGGGTTTGUUAUAGAAUATTTGTGGXGGAGUTUUATTTAGURGUURGTGAATTTUUATTUTGTTGUUTGGUAAURGGTTUAGAGGAGUTUAGRGUUUAAUUURGGUUUUTAUUURGUAUUUTTTUTUTGUURGTGUAGUTTGGGUTGUATTGATUAAAGGTTUAGUUTTTGGGGAU501UTUUAURGURGGUTRGUUUUUTGAGGAGGGGGUTGGGUUAGGGUUTRGGUTGAURGGGGAGGAAGAAGGGGAGUAGAGAAAAAUATGAGTUAUAGURGTGTGTUAUTGGAGRGUATTTUAATTUUUTGUATUAUAGGAGGTGTGGAAGGUXGUUTRGGGGAURGGGRGRGGGAGGTGRGUURGAGAAGGUUURGGGURGGUUTGUAGGGRGRGURGUTURGUUTGRGUUUTTTUUTUUUUUAURGUUUTUUURGUUATUTTUUUUTTTGGUTTUUTTUTRGUTRGGTGUAAUAAGTUTTT502AAAGAUTTGTTGUAURGAGRGAGAAGGAAGUUAAAGGGGAAGATGGRGGGGAGGGRGGTGGGGGAGGAAAGGGRGUAGGRGGAGRGGRGRGUUUTGUAGGURGGUURGGGGUUTTUTRGGGRGUAUUTUURGRGUURGGTUUURGAGGXRGGUUTTUUAUAUUTUUTGTGATGUAGGGAATTGAAATGRGUTUUAGTGAUAUARGGUTGTGAUTUATGTTTTTUTUTGUTUUUUTTUTTUUTUUURGGTUAGURGAGGUUUTGGUUUAGUUUUUTUUTUAGGGGGRGAGURGGRGGTGGAG503UUTGAAGAGUATTUTUUUTGAGTGUTUAATGATATGUUAGAGUATGTUTUAAATGRGGAGGATGGGGAGGURGGUTUUUTGGUAGATUTTUATGGAGAAGUTGAUTUUAGURGGUTTGTGTGUURGTUUUAGAGGAGRGGAAAUAGAGUXGAAGUUUAUAUUUUUAGGGUUUAGGUUUAGUUUTTUUAAGTURGGAGUTUAUUUAGUUTGUUUUTRGGUTUUTTUATUUTUUTUUAGAUAURGTUUUTTUTTUTGTUTUTGUATTTUUUATUUTUTURGUUUUTUUUTGTGUTGUTUTGT504AUAGAGUAGUAUAGGGAGGGGRGGAGAGGATGGGAAATGUAGAGAUAGAAGAAGGGARGGTGTUTGGAGGAGGATGAAGGAGURGAGGGGUAGGUTGGGTGAGUTURGGAUTTGGAAGGGUTGGGUUTGGGUUUTGGGGGTGTGGGUTTXGGUTUTGTTTURGUTUUTUTGGGARGGGUAUAUAAGURGGUTGGAGTUAGUTTUTUUATGAAGATUTGUUAGGGAGURGGUUTUUUUATUUTURGUATTTGAGAUATGUTUTGGUATATUATTGAGUAUTUAGGGAGAATGUTUTTUAGG505ATGTUTGGGAGGUUAAAAGUATUTUTUAGAUAGTUTUTAUAGGAUTUTTUUAGGTUURGGAAGUURGAGRGAGUTTUUTGGAGGAGGTGGUTGGGGAGAGTGGAGGAGURGGTAGGGGTRGUTGTGUTTGRGRGRGUURGTUUAGGAAUTXGURGGGGUTGTGGGGAGGGGGRGURGGUUTGGAGAGGAUAATGTAUAGTUTGTTUTAAUAUUUAUUUAUTUUAAARGUAUAUTTUUUAUUURGTUTUTTGTUUUTUUUAGUUURGGGGUTAGAUUUTGAGGGUTRGGGURGUAUUTUAU506GTGAGGTGRGGUURGAGUUUTUAGGGTUTAGUUURGGGGUTGGGAGGGAUAAGAGARGGGGTGGGAAGTGTGRGTTTGGAGTGGGTGGGTGTTAGAAUAGAUTGTAUATTGTUUTUTUUAGGURGGRGUUUUUTUUUUAUAGUUURGGXGAGTTUUTGGARGGGRGRGRGUAAGUAUAGRGAUUUUTAURGGUTUUTUUAUTUTUUUUAGUUAUUTUUTUUAGGAAGUTRGUTRGGGUTTURGGGAUUTGGAAGAGTUUTGTAGAGAUTGTUTGAGAGATGUTTTTGGUUTUUUAGAUAT507GGAGRGUTAARGRGUAGTGGGAGGGAAGGAGAGGAUTGAAGAGAGARGGGGGAGGGGAGAGGAGGGGTRGGUTGUUAGGUUTAGGTGGGGTGAATURGUAGUTGGGUTGAUTUAAGRGGAGGAGURGGAAGGAUAUUURGRGAGGUTTXGGGGRGRGUTTTTAGGGAGGRGURGUUTUUAGUTTTGTGUUAGAAAGTGGGGGTTGRGGUTUAGGUTTGAATUUAAGAAAGGUTURGGGTGGAAUTUUTGGGUAUUUTGGGTUUTTAUTUTGUUTTUAGGRGUTGGUUAURGTTGGGAUTT508AGTUUUAARGGTGGUUAGRGUUTGAAGGUAGAGTAAGGAUUUAGGGTGUUUAGGAGTTUUAUURGGAGUUTTTUTTGGATTUAAGUUTGAGURGUAAUUUUUAUTTTUTGGUAUAAAGUTGGAGGRGGRGUUTUUUTAAAAGRGRGUUUXGAAGUUTRGRGGGGTGTUUTTURGGUTUUTURGUTTGAGTUAGUUUAGUTGRGGATTUAUUUUAUUTAGGUUTGGUAGURGAUUUUTUUTUTUUUUTUUUURGTUTUTUTTUAGTUUTUTUUTTUUUTUUUAUTGRGRGTTAGRGUTUUU509TATUAGAATUUAUATAUUUAGGTGGGTTTAGGAUTTTUTAGGUUTUTUUUTUAGGUUATAGGAGUAUUUAUUURGGGUTUUTUTGGAGGGGUAGUUUUAAGGAAUUTGTTGGGGTAAUTTGTTTGUTUUUUAUAUUURGGGAATGTGUXGTUUTTTUAGGUURGUUUAUURGGATTUUTGTGUAGGGAGTUAGURGAUAUAGUATGTTGUATGTGUUUTGTGGGGAUARGTTUTGUUTUUTGTUAGGGGGAGGAGGUTGGRGGURGTGUUTGTGUTGURGUAUUTUAGUTUUUUAURGAA510TRGGTGGGGAGUTGAGGTGRGGUAGUAUAGGUARGGURGUUAGUUTUUTUUUUUTGAUAGGAGGUAGAARGTGTUUUUAUAGGGUAUATGUAAUATGUTGTGTRGGUTGAUTUUUTGUAUAGGAATURGGGTGGGRGGGUUTGAAAGGAXGGUAUATTUURGGGGTGTGGGGAGUAAAUAAGTTAUUUUAAUAGGTTUUTTGGGGUTGUUUUTUUAGAGGAGUURGGGGTGGGTGUTUUTATGGUUTGAGGGAGAGGUUTAGAAAGTUUTAAAUUUAUUTGGGTATGTGGATTUTGATAU511AGAGGATTTAAGAUTUAUUUAGGGUAAAUAUTGGGAUUAUTGTAAGAGRGUTGGAAUATTUTGUUTUTTGAGTGAAGGGGUUTTUTTTUTAGUUTUTATGGUAUTGAGGGGTGRGURGGUTGGTGGAGGAGUAGTURGATGGAGUUUTGXGTTUUURGGGGAUAUAGGGUUAAGUTTTGAGGTGGAAAGTTTUTGGTTUTGAAAUAAUAAGGAGAGAGTUTGTTTTTUTTUUTAAAATTTGGAUTUTTGTUTGUAUAAAUTUTGGTUTGTTTTGUARGGTTTGTGTGUUTTTTTTTUUUT512GGGAAAAAAAGGUAUAUAAAURGTGUAAAAUAGAUUAGAGTTTGTGUAGAUAAGAGTUUAAATTTTAGGAAGAAAAAUAGAUTUTUTUUTTGTTGTTTUAGAAUUAGAAAUTTTUUAUUTUAAAGUTTGGUUUTGTGTUUURGGGGAAXGUAGGGUTUUATRGGAUTGUTUUTUUAUUAGURGGRGUAUUUUTUAGTGUUATAGAGGUTAGAAAGAAGGUUUUTTUAUTUAAGAGGUAGAATGTTUUAGRGUTUTTAUAGTGGTUUUAGTGTTTGUUUTGGGTGAGTUTTAAATUUTUTT513TGUUTUTGAGTUTAAAARGGUAGTGGUUTAGGAGUAUAGGGUUTGGGGGUAGGGGUAGTGUUAUAUUTAAUUTGAGATATGTUUAGAGUTGAGGTUTAGUTUAUAGUATUTGTGRGTRGGGGAAGUTGGUTGRGGTUARGGURGGTGUAGXGGUUUAAGGAGTUUAUAAAGUAGTAAUUTTGGUUUAUAUUAUAGUTURGGTGUATTTGGAGAGGGGGUUUAGTUTAGGUTGAAGTTGGGGGGAGUUTGGUUAGGGUUTGGGUAUUAGGRGUAGGAUAGAGGGAAAGGUUTUUAGUTUUT514AGGAGUTGGAGGUUTTTUUUTUTGTUUTGRGUUTGGTGUUUAGGUUUTGGUUAGGUTUUUUUUAAUTTUAGUUTAGAUTGGGUUUUUTUTUUAAATGUAURGGAGUTGTGGTGTGGGUUAAGGTTAUTGUTTTGTGGAUTUUTTGGGUXGUTGUAURGGURGTGAURGUAGUUAGUTTUUURGARGUAUAGATGUTGTGAGUTAGAUUTUAGUTUTGGAUATATUTUAGGTTAGGTGTGGUAUTGUUUUTGUUUUUAGGUUUTGTGUTUUTAGGUUAUTGURGTTTTAGAUTUAGAGGUA515GUAGUUUTGGGGRGTGGGGGGRGGUTGTTTUUTGUTGUUUUTTGGGUTGUUAUUTGUURGAGUTGUUAGUUAUAGTTGGAUTTUUTTUUAGUUUTURGGGGTGUUTGUATTUUUAUATTRGAGAUAGGUAGTGAGAGGGAGTGAGGGGXGATGATGTUTGUAGUUUAUAAGAGUUTURGGGUAGTAGUUAGGUUUUTUTGUTUAGUUTGAUUTGUUTGGUUTUUAGUAGGGTGUTATGGUUUTGGGAGGUUUTGGUTTUTGUUUUUTTTUUTUUUUTGUUUTGRGUTUTGUTUTGUTGTG516AUAGUAGAGUAGAGRGUAGGGUAGGGGAGGAAAGGGGGUAGAAGUUAGGGUUTUUUAGGGUUATAGUAUUUTGUTGGAGGUUAGGUAGGTUAGGUTGAGUAGAGGGGUUTGGUTAUTGUURGGAGGUTUTTGTGGGUTGUAGAUATUATXGUUUUTUAUTUUUTUTUAUTGUUTGTUTRGAATGTGGGAATGUAGGUAUUURGGAGGGUTGGAAGGAAGTUUAAUTGTGGUTGGUAGUTRGGGUAGGTGGUAGUUUAAGGGGUAGUAGGAAAUAGURGUUUUUUARGUUUUAGGGUTGUU517TUTUTUUTGGGUUAAGUTTTGTGGATGUUUAGUUTGGGGURGRGGGGAGUTGGUAGGTUAGTGGUAGAUAUTGGTGGGUAGAUUTAGTGTUTGGTAGAAUAGGUATUAAGGAAGTGGTGAURGGAGGGAAGUUAAGTGUAUTUAAAUUUTXGGGTGAGTUATUAURGURGGGTUTTTUAUAGUTGUTGAAAGTGAGUAAUAGTGATGAAGGTTTGTGAGTTTUTGRGTGAGRGAGTGAATGGAUUAGTAGUAGTTTUUAGGTTGTGGAAGAGRGTTUUUTUUURGGGATGGGGAUAUTTG518UAAGTGTUUUUATUURGGGGAGGGAARGUTUTTUUAUAAUUTGGAAAUTGUTAUTGGTUUATTUAUTRGUTUARGUAGAAAUTUAUAAAUUTTUATUAUTGTTGUTUAUTTTUAGUAGUTGTGAAAGAUURGGRGGTGATGAUTUAUUXGAGGGTTTGAGTGUAUTTGGUTTUUUTURGGTUAUUAUTTUUTTGATGUUTGTTUTAUUAGAUAUTAGGTUTGUUUAUUAGTGTUTGUUAUTGAUUTGUUAGUTUUURGRGGUUUUAGGUTGGGUATUUAUAAAGUTTGGUUUAGGAGAGA519GGUTGGTUTTGAAUTUUTGGGUTUAAGAGUTUUAUUTGUUTUAGUUTUUUAAAGTGAGUUAUUAGGUUTAUURGGTUUTTTTUUTUUATGUTTUTGTGGUUTTTUUTUUTGTTTAGXGAGUTUTGAUATTUAUTUATAGGTAGGAAUAAAGUUUTUUATTGGTTAGTUTGGGUTGAGGTGGGXGTGTGTGTTTUTGTATUAGTGATUTGTTTTURGGUAGGUUTUTUUUTGAGGGGAGAGUTGGTAGUTTUUATGTAAGTGGUAGGGUATAUTTUAUTAAATAAAAGATGTGTGGGTGAG520UTUAUUUAUAUATUTTTTATTTAGTGAAGTATGUUUTGUUAUTTAUATGGAAGUTAUUAGUTUTUUUUTUAGGGAGAGGUUTGURGGAAAAUAGATUAUTGATAUAGAAAUAUAUAXGUUUAUUTUAGUUUAGAUTAAUUAATGGAGGGUTTTGTTUUTAUUTATGAGTGAATGTUAGAGUTXGUTAAAUAGGAGGAAAGGUUAUAGAAGUATGGAGGAAAAGGAURGGGTAGGUUTGGTGGUTUAUTTTGGGAGGUTGAGGUAGGTGGAGUTUTTGAGUUUAGGAGTTUAAGAUUAGUU521UAAGUATUTTAGTGATGTGAGTUATUAAAAUTTUUTUUTGGGTUTGUTTTGAGUUUUAUUTTUUTUUTUUTGUAGTUATGUTUTTAGUUTUAGGGUUUTGGGGRGGARGUURGGAUAUTUUUUUAGUAGUUTGUTTTUUAGAGGUUAUTGXGUTGUTUAGUTURGGGGGUURGTUUTURGTGGATUUUTUUAGGUUUAGUAGAGTGTTTGAUUARGGGUUTGAURGGGAGGGGAGARGUUAUUTUUTGGGGAUTTGUAUUUUAAUUAGUAUUAUTGTUATGAGAUAUURGGAGGUUAGUA522TGUTGGUUTURGGGTGTUTUATGAUAGTGGTGUTGGTTGGGGTGUAAGTUUUUAGGAGGTGGRGTUTUUUUTUURGGTUAGGUURGTGGTUAAAUAUTUTGUTGGGUUTGGAGGGATUUARGGAGGARGGGUUUURGGAGUTGAGUAGXGUAGTGGUUTUTGGAAAGUAGGUTGUTGGGGGAGTGTURGGGRGTURGUUUUAGGGUUUTGAGGUTAAGAGUATGAUTGUAGGAGGAGGAAGGTGGGGUTUAAAGUAGAUUUAGGAGGAAGTTTTGATGAUTUAUATUAUTAAGATGUTTG523TGATGAUUAGGUAUTGUTATTUTTTAGGURGGGATTTUUUUAAGUUTTGGTATTTTTAAAAATARGTTATAGTTUUUTTGAAAUTUTUTUUTTATUAUUTUUAUUTTUUTGTTTTUATUTUUUAUTUUTTGGUAUUUTUTGTUTUUUUAXGGTGTUUUUATGARGUTGUUTGUATGUUUATTGGUUUUAGUUTGGGAGUTTUTUAGAGARGUURGGGUUAGAUATGGUTGUAGATAGAGUUAAGAGGGTGGUUTRGGGTGGUTGGTGGUAGTUTUUTGGUTGTGGGGGUAGAAGTGGGGG524UUUUUAUTTUTGUUUUUAUAGUUAGGAGAUTGUUAUUAGUUAUURGAGGUUAUUUTUTTGGUTUTATUTGUAGUUATGTUTGGUURGGGRGTUTUTGAGAAGUTUUUAGGUTGGGGUUAATGGGUATGUAGGUAGRGTUATGGGGAUAUXGTGGGGAGAUAGAGGGTGUUAAGGAGTGGGAGATGAAAAUAGGAAGGTGGAGGTGATAAGGAGAGAGTTTUAAGGGAAUTATAARGTATTTTTAAAAATAUUAAGGUTTGGGGAAATUURGGUUTAAAGAATAGUAGTGUUTGGTUATUA525GUUTAGUUURGRGRGUAUATAUARGTGTGUTUTURGRGRGGAUUTRGGGAAUTTTGUUUTUARGUURGRGGRGRGUTTGUUTUURGUURGUUURGGUUTUUAUUUUTTRGAGATGUUUUTTUUUUAGURGGTUTUUUUTUUUUURGGUTXGGGAAGAAGUUTGUTGGGUUAGGGRGUUUTGAUUAUUTUUTRGGAGGURGGUAAAUUTGUUTGAAURGUUUUAGAGGAATRGGGUAGGGGUTRGUAUUUUAUUURGGUAGGAGGGUUURGAGAURGAUURGGGURGGGGUTURGUAGURG526RGGUTGRGGAGUUURGGUURGGGTRGGTUTRGGGGUUUTUUTGURGGGGTGGGGTGRGAGUUUUTGUURGATTUUTUTGGGGRGGTTUAGGUAGGTTTGURGGUUTURGAGGAGGTGGTUAGGGRGUUUTGGUUUAGUAGGUTTUTTUUXGAGURGGGGGGAGGGGAGAURGGUTGGGGAAGGGGUATUTRGAAGGGGTGGAGGURGGGGRGGGRGGGAGGUAAGRGRGURGRGGGRGTGAGGGUAAAGTTUURGAGGTURGRGRGGAGAGUAUARGTGTATGTGRGRGRGGGGUTAGGU527GAAARGGRGGTRGUAGUUUTRGGURGGGUARGRGTGGGGURGTTRGTGGAGRGGTGTUTTGUTAGGURGGTTGGGGTAUTTGRGGGGURGGATGGGUTTGAGGGTGAGXGGRGGUTGGGGUAGGUTGUUAAAGUURGGGTGGATUTGUTTGTUTTTGAATGUUTTGATGGTUTUUAGAGGGGTAATAGGGGGXGGGTTGAUURGGATGGGGTUUATGUUUTGGAAGGGUTTGTGUTURGGAATGGAGUUUATGTRGTTGGGGTGGTGGTAGAGGTTGTAGTUAGGAATUATGGGGAAGAG528UTUTTUUUUATGATTUUTGAUTAUAAUUTUTAUUAUUAUUUUAARGAUATGGGUTUUATTURGGAGUAUAAGUUUTTUUAGGGUATGGAUUUUATURGGGTUAAUUXGUUUUUTATTAUUUUTUTGGAGAUUATUAAGGUATTUAAAGAUAAGUAGATUUAUURGGGUTTTGGUAGUUTGUUUUAGURGURXGUTUAUUUTUAAGUUUATURGGUUURGUAAGTAUUUUAAURGGUUTAGUAAGAUAURGUTUUARGAARGGUUUUARGRGTGUURGGURGAGGGUTGRGAURGURGTTTU529TGUUUAGGUTGGAGTGUAGTGGUAAAATUTTGGUTUAUTTUAAUUTURGUUTUURGGGTTUAAGUAATTUTUUTGUUTUAGUUTUTUAAGTAGUTGGGATTAUAGGUATGUAUUATUAUAUUUAGUTGATTTTGTATTTTTAGTAGAGAXGGGGTTTUAUUARGTTGTTUAAGUTGGTUTUAAAUTUUTGAUUTUAGGTGATUUAUURGUUTTGGUUTUUUAAAGTGURGGGATTATAGGTGTGAGUUAURGUAUUTGGGUAATTAGTATTGTATTTAAGAGTTTATATTUATATUUATA530TATGGATATGAATATAAAUTUTTAAATAUAATAUTAATTGUUUAGGTGRGGTGGUTUAUAUUTATAATUURGGUAUTTTGGGAGGUUAAGGRGGGTGGATUAUUTGAGGTUAGGAGTTTGAGAUUAGUTTGAAUAARGTGGTGAAAUUUXGTUTUTAUTAAAAATAUAAAATUAGUTGGGTGTGATGGTGUATGUUTGTAATUUUAGUTAUTTGAGAGGUTGAGGUAGGAGAATTGUTTGAAUURGGGAGGRGGAGGTTGAAGTGAGUUAAGATTTTGUUAUTGUAUTUUAGUUTGGGUA531TGTTAUTTUATTGAATTUTUATAATAGUTTAATGUTATRGGTTTTUTTUTTAATTTTGGGGGUATAGTGGGGAGATAAGUAAAUTGATAUUURGGAGGTTGAGTGAUTUATTUATGGAATGUAGUAGGUURGTGAGTUAAAGXGAGTAUATGGUAAGAUXGAGTGAAGUTGGGGAAUAATAGUUAAGUUAAGAGRGTTTTAAAGATAUTTAGUATUTTUATUAUAUTGAATUUTAAGGTGAUAGUAUTTUUAUTRGAUAGUAAAATGTUAGATTUAAUTGTTTUTTTURGGTUTTUAAAU532GTTTGAAGAURGGAAAGAAAUAGTTGAATUTGAUATTTTGUTGTRGAGTGGAAGTGUTGTUAUUTTAGGATTUAGTGTGATGAAGATGUTAAGTATUTTTAAAARGUTUTTGGUTTGGUTATTGTTUUUUAGUTTUAUTXGGTUTTGUUATGTAUTXGUTTTGAUTUARGGGUUTGUTGUATTUUATGAATGAGTUAUTUAAUUTURGGGGTATUAGTTTGUTTATUTUUUUAUTATGUUUUUAAAATTAAGAAGAAAAURGATAGUATTAAGUTATTATGAGAATTUAATGAAGTAAUA533TTAGTATTAUUAAATATRGAGTUAAGGGUUTGATUAGUUUUAAAAGAATGAGGUAUTTTTAATGTGAUAUUATTUUTGGUAGTUTUAGGTTRGGUTUTUUUAGGUUURGGATGUAGATGGUTGTTAGGGGUTGGUUATUUTUATUTUAAXGGTUUTGGAAGGUAUUAUTTTUAGGGUATATGUUATGAUTAAUATTURGGTGAGUAATGUTGAUTUAATRGTAGAUTGTTATTTUATGTTUUUAGTAUUUTGTGUAGGAAGGGAAGGGAAATGAGTAATAGATGTATUAGTUUUATTUAA534TTGAATGGGAUTGATAUATUTATTAUTUATTTUUUTTUUUTTUUTGUAUAGGGTAUTGGGAAUATGAAATAAUAGTUTARGATTGAGTUAGUATTGUTUAURGGAATGTTAGTUATGGUATATGUUUTGAAAGTGGTGUUTTUUAGGAUXGTTGAGATGAGGATGGUUAGUUUUTAAUAGUUATUTGUATURGGGGUUTGGGAGAGURGAAUUTGAGAUTGUUAGGAATGGTGTUAUATTAAAAGTGUUTUATTUTTTTGGGGUTGATUAGGUUUTTGAUTRGATATTTGGTAATAUTAA535AGTGGTGGUTGUTGTTTUTRGGTGGUAGAGATGATGUUTGGTTTATTUTTAGTAAAGTGUTTAGGARGUTGAGUUTGAGGGGUTUTGGAATGGAAAAAUAAAAUAAAAUAAAAUAAAURGGAGGUURGUTUTGUUTGGUTUUTAGAGAUAXGUAAAGUTGGGUAAAGGAAGGAGATTGAGGTGGGAUTGAGAUATTGTTGUATTGTGAATGUUURGGTTUUUUAUUTUUTGUUUUURGAATUATGATTGTTTTATGRGGTTATTTTTUUUTTTGGTGAGGAAAATGGGATGTGGTGTUAA536TTGAUAUUAUATUUUATTTTUUTUAUUAAAGGGAAAAATAAURGUATAAAAUAATUATGATTRGGGGGGUAGGAGGTGGGGAAURGGGGUATTUAUAATGUAAUAATGTUTUAGTUUUAUUTUAATUTUUTTUUTTTGUUUAGUTTTGXGTGTUTUTAGGAGUUAGGUAGAGRGGGUUTURGGTTTGTTTTGTTTTGTTTTGTTTTTUUATTUUAGAGUUUUTUAGGUTUAGRGTUUTAAGUAUTTTAUTAAGAATAAAUUAGGUATUATUTUTGUUAURGAGAAAUAGUAGUUAUUAUT537GGGGTRGGUATGGGUTGGAGUTUAGAGARGGUUAGUTAGGAUTTUAGGAUAUAUAGUAAAUTAGUTGRGUUURGUTGAGGGTUAGRGUAUAGURGUUUAUAUAAGGTGTUUTUTUUURGGGUTUTUTGGGURGURGGUUTUUTGUTTUUXGTGURGUAGAURGGGATTAGAUTGTGGARGRGGGGAAGGAAGGGGGRGTTGRGARGGGATUTTGAGGGGAGUAGGAUTTGUUUUTGUUUUTGRGGRGAAGUTUTAGGUUUTGGUAAGGTTRGGTAUAURGGGGGURGUTUUTUUUUAGGG538UUUTGGGGAGGAGRGGUUUURGGTGTAURGAAUUTTGUUAGGGUUTAGAGUTTRGURGUAGGGGUAGGGGUAAGTUUTGUTUUUUTUAAGATUURGTRGUAARGUUUUUTTUUTTUUURGRGTUUAUAGTUTAATUURGGTUTGRGGUAXGGGAAGUAGGAGGURGGRGGUUUAGAGAGUURGGGGAGAGGAUAUUTTGTGTGGGRGGUTGTGRGUTGAUUUTUAGRGGGGRGUAGUTAGTTTGUTGTGTGTUUTGAAGTUUTAGUTGGURGTUTUTGAGUTUUAGUUUATGURGAUUUU539GTGUARGUAGGGAAATAUUTUAUAGGGTAAATTTGGATURGATTGAGAAUAGGAAGUUAUAGGUUAATAUAAGGAGGUTUTGTGAGAAUAGATGAUAAAUUAUAAGURGGGGAGGGGGAGGAAAGAGUTTTUTGGGUUTGGGGGATGGGXGAGUURGUUAGUAUAUUAUAUAUAGUTGRGUTTGGUUTUAGTAATUAAAAUUATUATTAUAGAUUTGARGGTTTGGUTGUAGUTGTAAAGAGATAAGUATGTTGGAAGAGAAAAUAGGGUUURGGTGAUURGGUUTTAGGGTUTGAGRGU540RGUTUAGAUUUTAAGGURGGGTUAURGGGGUUUTGTTTTUTUTTUUAAUATGUTTATUTUTTTAUAGUTGUAGUUAAAURGTUAGGTUTGTAATGATGGTTTTGATTAUTGAGGUUAAGRGUAGUTGTGTGTGGTGTGUTGGRGGGUTXGUUUATUUUUUAGGUUUAGAAAGUTUTTTUUTUUUUUTUUURGGUTTGTGGTTTGTUATUTGTTUTUAUAGAGUUTUUTTGTATTGGUUTGTGGUTTUUTGTTUTUAATRGGATUUAAATTTAUUUTGTGAGGTATTTUUUTGRGTGUAUA541TGTGRGGGUAGTGGGTTGTGRGGGUAGTGGGTTGTGUATURGGATGTGTAGUAUTUAUAUAUTTRGGGTGAUTUTTUUTGGGTAAGUTGTGGATGTGAGTGGGGGUAGUATUTGURGTGAUTUATTUTUTUUTUTTTUUATTUUAAGUXGGGTGGGGGAGTTTGGGATTTUUAGAUAAGGUUTGGUTUUUUUTGGUAUAGAGGGTGGGAGTGGGGATGGGGAGGGAGGAGGGAAGGGTUATGGGAAGGTGGGGUUATGTTTTGTGUTUAATGAAUTGAGAAGGGGGAGGGTTUUAGUTGG542UAGUTGGAAUUUTUUUUUTTUTUAGTTUATTGAGUAUAAAAUATGGUUUUAUUTTUUUATGAUUUTTUUUTUUTUUUTUUUUATUUUUAUTUUUAUUUTUTGTGUUAGGGGGAGUUAGGUUTTGTUTGGAAATUUUAAAUTUUUUUAUUXGGUTTGGAATGGAAAGAGGAGAGAATGAGTUARGGUAGATGUTGUUUUUAUTUAUATUUAUAGUTTAUUUAGGAAGAGTUAUURGAAGTGTGTGAGTGUTAUAUATURGGATGUAUAAUUUAUTGUURGUAUAAUUUAUTGUURGUAUAA543GUAAUTGGRGUTGGGTAGGUAAAGURGGGAGAAAUTGUTGAGARGAGGTTAGGATTTAAUUTTTAAATTUTGGAGUUATRGGAAAURGAGGGGAGGARGARGGGTGTRGGTGUTAATGAGGUTGGGGGRGGGRGATGRGRGGTGGGUUTUXGAGTURGGGGUAGGTUTRGGGGGTTUUURGGGGAAGGUUUTGGGAGUUUTTGGUUUTGGRGGUUTURGUUATUAGAUTGGGAATGTUTUTGATTGGGTGGUUAGGAGGRGGTGGUUUTUUTUUURGUUUAGUTGAGGGGTGTRGTUTTU544GAAGARGAUAUUUUTUAGUTGGGRGGGGAGGAGGGUUAURGUUTUUTGGUUAUUUAATUAGAGAUATTUUUAGTUTGATGGRGGAGGURGUUAGGGUUAAGGGUTUUUAGGGUUTTUUURGGGGAAUUUURGAGAUUTGUUURGGAUTXGGAGGUUUAURGRGUATRGUURGUUUUUAGUUTUATTAGUAURGAUAUURGTRGTUUTUUUUTRGGTTTURGATGGUTUUAGAATTTAAAGGTTAAATUUTAAUUTRGTUTUAGUAGTTTUTUURGGUTTTGUUTAUUUAGRGUUAGTTGU545GGGUAUUUTUTGGTGUTTUUAGGUUTGTGAATTGGUAUAGUAGGAUUAUAGAUUTUUAAGGTGUUUAUUTGGGGGUTUAGAAUUUTGGRGGGGAAGGTUAGTGUTATUUUAURGGAGAAGAGAUUTAGTUTAGUTGAGUUUUTGGUUAGXGGUAAGGAGGAAAGGATGAAUATUAGUUARGUUTGGUAUTGAUTGUUAUAGUUAGAGUUTRGUUUAGUUUAAGAATGTTTUTGTTUTAAGAUTTTTTTUTTTTTTGTATTTTAGAAATTATUAUAGGUAAATGTUAUUTTGAAGAUURGG546URGGGTUTTUAAGGTGAUATTTGUUTGTGATAATTTUTAAAATAUAAAAAAGAAAAAAGTUTTAGAAUAGAAAUATTUTTGGGUTGGGRGAGGUTUTGGUTGTGGUAGTUAGTGUUAGGRGTGGUTGATGTTUATUUTTTUUTUUTTGUXGUTGGUUAGGGGUTUAGUTAGAUTAGGTUTUTTUTURGGTGGGATAGUAUTGAUUTTUUURGUUAGGGTTUTGAGUUUUUAGGTGGGUAUUTTGGAGGTUTGTGGTUUTGUTGTGUUAATTUAUAGGUUTGGAAGUAUUAGAGGGTGUUU547UTUATGGAGAGGAGUAGAGATGUAGGAAARGUAAUAGUAGUARGGUAGAAARGUAGGAGAAAUAGUUURGUUTUAGAGURGUUUAUUTUUTUURGUUATGUUAGGAAGGGUUAGTGTUUUTUUAGARGURGGTGAUTGTUARGTUAGAUAXGTGARGTGTGGUTGTGUUUAGATTUTTGGRGGTGAGUUURGGRGAGGGAUUUAGRGGTUTUURGGRGTUTGGTTTAGGGGGGGATUTURGUAAGAUUURGUURGUARGTGGUTUUTGTGAGGGGUAUTGRGRGRGAAGGUTGTGGTUTG548UAGAUUAUAGUUTTRGRGRGUAGTGUUUUTUAUAGGAGUUARGTGRGGGRGGGGTUTTGRGGAGATUUUUUUUTAAAUUAGARGURGGGAGAURGUTGGGTUUUTRGURGGGGUTUAURGUUAAGAATUTGGGUAUAGUUAUARGTUAXGTGTUTGARGTGAUAGTUAURGGRGTUTGGAGGGAUAUTGGUUUTTUUTGGUATGGRGGGAGGAGGTGGGRGGUTUTGAGGRGGGGUTGTTTUTUUTGRGTTTUTGURGTGUTGUTGTTGRGTTTUUTGUATUTUTGUTUUTUTUUATGAG549UTUTUUAUTGTGUAGGUUAUUTGTAGGGAUAGTGUUAGTGGGTGTAGGAGAGGTGGRGAGGUTGUAGUAGTGRGGGATGGGUTUUUUAUAUUUUUAAATAUTUUAUATGGGGTURGGGGUUTTUUUAGGAUUTGGGUUAGGTGXGUAXGUUTGGGXGGGGUUAGUUAGUTRGTGUTGAGTUAURGGGTGURGTUAGTGAGGGUUTGGUUUUAUUUTRGGGAAUUAURGGTGUTGGTTTTUUUARGGUTGUTGUURGUTGTGGGUUTTGUTGTUAUUUAUAAGGUUUTGGGAGGUUUTGUU550GGUAGGGUUTUUUAGGGUUTTGTGGGTGAUAGUAAGGUUUAUAGRGGGUAGUAGURGTGGGAAAAUUAGUAURGGTGGTTUURGAGGGTGGGGUUAGGUUUTUAUTGARGGUAUURGGTGAUTUAGUARGAGUTGGUTGGUUUXGUUUAGGXGTGXGUAUUTGGUUUAGGTUUTGGGAAGGUUURGGAUUUUATGTGGAGTATTTGGGGGTGTGGGGAGUUUATUURGUAUTGUTGUAGUUTRGUUAUUTUTUUTAUAUUUAUTGGUAUTGTUUUTAUAGGTGGUUTGUAUAGTGGAGAG

Also provided herein is a deoxyribonucleic acid identical to 5-10,10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110,110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190,or 190-200 of contiguous nucleotide sequence of the sequence including asequence of SEQ ID NO:1 to SEQ ID NO: 550.

In embodiments, provided herein is a deoxyribonucleic acid whichincludes a methylation site set forth in Table 1.

In embodiments, included herein is a deoxyribonucleic acid in which aplurality of methylation sites set forth in Table 1 are methylated orunmethylated. In embodiments, the plurality of methylation sitescomprises at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50,75, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 550 methylationsites. In embodiments, the plurality of methylation sites comprisesbetween 1-50, 50-100, 100-250, 100-300, 100-400, 100-500, 100-550,250-550, or 350-500 methylation sites.

Compositions for Detecting Methylation

Also provided herein are probes and primers that are complementary toone or more of SEQ ID NOS: 1-550. In embodiments, pairs of primerscomplementary to nucleotide sequences on either side of a methylationsite of interest listed in Table 1 are provided. In embodiments, aplurality of probes and/or primers are provided to detect and/or amplifya polynucleotide (e.g., a polynucleotide obtained by bisulfite treatmentof DNA) comprising a methylation site of interest. In embodiments, aprobe or primer is complementary to a polynucleotide sequence thatencompasses the methylation site of interest. In embodiments, the probeor primer is complementary to a sequence that is proximal to themethylation site of interest (e.g., within 1000, 900, 800, 700, 600,500, 400, 300, 200, 100, 75, 50, or 25 nucleotides of the methylationsite of interest in a genomic or bisulfite-treatment-derivedpolynucleotide).

In embodiments, a deoxyribonucleic acid selected from SEQ ID NO:551 toSEQ ID NO: 782 is included. In embodiments, the deoxyribonucleic acidselected from SEQ ID NO:551 to SEQ ID NO: 782 is hybridized to acomplementary DNA sequence having uridine or cytosine. In embodiments,each of the nucleic acids is different. In embodiments, each of thenucleic acids does not simultaneously have the same sequence selectedfrom SEQ ID NO:551 to SEQ ID NO:782.

In embodiments, aspects include a deoxyribonucleic acid selected fromSEQ ID NO:551 to SEQ ID NO:782, hybridized to corresponding acomplementary DNA sequence having uridine or cytosine, and in a complexwith an enzyme, e.g., a thermostable DNA polymerase. In embodiments, thethermostable DNA polymerase is Taq DNA polymerase.

In some aspects, the method includes deoxyribonucleic acid that has asequence that is at least 50%-55%, 55%-60%, 60%-65%, 65%-70%,70%-75%,75%-80%, 80%-85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% ormore identical or homologous to a nucleic acid having a sequence of atleast one of SEQ ID NO:551 to SEQ ID NO:782.

TABLE 5 SEQ ID NO: Sequence, 5′ to 3′ 551 GGGAGAAGAGATTGGAAAA 552CTAAAAACCTAACACTAACAACATAAT 553 TGTTGTTTAAAATGTTGTTT 554AACCCTAAATAATTCTTCTC 555 GGGTTGGGTTGAGGTTTT 556ACACCTTACATCTCATTTACAACTC 557 AATTTGTGAAAAGTTTGTGTA 558CCCAATCACCTTTAATCT 559 GTTGGGATTTGAAATAGTGA 560 CCTCCACTCACCTAAAACTT 561TTGGTTAGTGATTATTTATT 562 AAAAATTAATATAAAATTAAAA 563 TTTGTAGGGAGTTAGGGAT564 TCCTCTATCTCACCCTAAAT 565 TTTGATTGAATTATTTGTGTATT 566ACTCCCTTACTCCTAAACACT 567 AGTGGAGATGGTAGGGAGA 568CCCAAAACTAAAACCAAATATAA 569 TTGTGGTTAAATTTATTG 570 ACCCAACAAAATAATATC571 TGAGGTAGAGTTGTGTGTATAT 572 ATCAATCAATTCTCATTAAAC 573GGAAGTTAGGAAGGGTTGT 574 CTCCAACTCCAACTAAAACTC 575 TTGGGTATTGATTTATTTT576 AAATTCTACCTACAAACTATACA 577 AGGATGAAGTAATAATTAAATATTG 578CCCACTCTACCAACTAAAC 579 AGGTTTGTGTTAGTATAAAT 580TTCTTACCTATATAATTAATAATA 581 GTTGGGTGAATTTTATTAG 582TCAAAACCTAAACTCTAACA 583 GGATTGGTTTTATATAGAAAGTAT 584CAAATAATAAATCATAACTCTTAACT 585 TGGGGTAGTTGATGGTTT 586CTTTCTAACAAAATAAAAAAATTTAA 587 TTGTATTTGAAGTTTGTAGAGATTTATA 588TTTCCTCCAACAACTCAAT 589 TTATGAGTATGTAGTAGGGTTATTATA 590AAAATATCAAACAAATTTATCC 591 TGGTTGTTTGTTTTTTATGTATT 592TCCCTACCTCCCAAATTC 593 TATGATGATTGTTGTAGTGTAGA 594CCTCCCTAATAACTAAAAATAC 595 GGTGGTTTTGATATTTAGTG 596 CCCAATTACCTAACAAATTA597 TGGGATAGGTGTAGATATG 598 CAACAAAAACTAAAACACTATAC 599TTTGGGATTGGTTATTTT 600 AAACCCCTTAACTCTATACC 601 GATTTTTTTGAGAAGAGTATAG602 AACCACTACCACCTAAATATA 603 GGAGGATAGGGTGTGATT 604ACATTTTTAACTCTAACTAAAAATAAA 605 TGGAAATGAGGTGAGTTT 606AAAAAAAAATAAAATAACAATAACTA 607 TGGAGAGTTTAGTTTGTTT 608CAAAAAAAAATCTAACAAC 609 TGGGTTTTAGTTATGTGGTT 610ATCAATAATATCCAACAAAATAATAT 611 TTTTTTTAGTTTTTGTATATATATTAG 612ACCCAAATAATCAACTCTT 613 GTGGTTTTTGGAGATTTA 614 AAACAAACTACAAATAAAATAATAC615 GGGTTATAGGTTTGAGTTA 616 CCATTAAAAAAAATAAAATC 617TTGGTAGATTTAGTAAATTTATT 618 AAACTTAAACAACCCTATATAC 619ATGGTTTTAAAGAGTAGTAGTATAGTT 620 AAATTTACTCATCCCACTTC 621AGGGGTTGGGATATTGTT 622 AAAAATTTCTCCTACAAAAAACTAA 623ATGGGTGTTTGGAATTTTTA 624 CTACCTCAACCTCCTAAATAACTAA 625GTGTTTTGTGGTAAAGATATAG 626 ATTCTTAAATTAATTCAACTACAT 627TGGGGGTAAAAGTTATAGTT 628 AAAAAACAAAAAACCAAATAC 629 GTTTTTTGGTTAGTGTGTT630 CCCCATACTTCTATACTATAAT 631 TTGTTGTTTTTAAAGAAATTATA 632ATCATCTAAACTTAACTCATCTAA 633 ATTTTTGGGTGTTTTATATT 634 AAACCTCAAACAATAACA635 ATTAAGGATATTTAGGAGAGTAAG 636 ACACCACAACTTCAAACTAC 637TGAGGAAGAGAGAAGAGATGATA 638 AAAACTAAACTATAAAACAAAACAAAACTA 639GGTGGAGGTGTTTTTTATAG 640 CCAAATACTACTTTCAAAATACA 641ATGGATTATTATTGTGTTATT 642 CATCTCAACCTCATACTAA 643 GGATGATTTAGTAGGGATTGAG644 CCAAATAAAAACCATTCTCTAAC 645 TTGGATTAAGTATTTTTGATATTA 646TCCCTAAACCATATATTACTAAA 647 GGGTAGTTTGGTGATTATTATT 648CCCTTCCCTACTCACAATA 649 ATTTGGTTAGTGATTTAGTTATT 650TCCCACTTAAAAAATTCTATA 651 AGTGGGGAAGGTAATTGTTAT 652CTTTCTAATAAAAATTTACTAAAACCTCTA 653 TTTGGTTAGTTTTATTTTTGATTG 654ATTCCTCCCTATCCCTATTC 655 GGGATAGGGGTTAGAGTAA 656 TCCATAAAAACAAAACACTC657 TTTTTTAGTATGAGTTATAAATTAT 658 AAAACAAAATCTACCTATATATT 659TTTTATTAATAAAGTAGGTATGA 660 ACCTTTCTCAAAATTACTAA 661ATAGGGTTGAGGTTAGAGTTAT 662 CCTCCTCTCCACAATAAA 663TTTAAGTTTTTTTTTAGTTTTGTAGT 664 CCCCATCCTCTCTATCTC 665AAATTTAAAATTTAGAGGTTTTTATA 666 AAACTTCACACACAAATCTATATT 667TTTTTATTTTATTTTTTATTTTTAA 668 ATACCTCCCTAATTATATTATTAA 669TTTTAGAATATTTAAAGAAGTTAGT 670 TAACCTCACTTTCCTATCA 671AATTTAGTATAAGATTTGATTTGTTA 672 CCACCTACTCCTTCCTATAC 673TTTTTTGAAATTGTATGTTAT 674 CAAATCCTTAAAATTCTATAA 675 TTTGAAGTGGTGTTTTAG676 CCAAAATTCTTCCATACT 677 TGGGTATTTAGTTTTTTGTG 678AACAACTACCTCCTTTTACTAAT 679 TATGGTAGGAGGTGGAGTT 680 CCCAATTTTAAAACAATAC681 AGAGGAAGTAAGGTTATTAGTT 682 ACCAAACAAACAATATCTAA 683GGTTTTAATTATGATTTAATTAGA 684 CCTACACTCAAATTTACCTCTA 685AATGGGTAGTTGATATAATTATT 686 CACAAAATCCTAAAACTAAAA 687AGGATTAGTGGAAATGAAAATA 688 TAACCTCAAAACAACTTCTAAAC 689TTTTTTTTATAGAGAAGTATTTTAG 690 CCCATTACAAAACTATCC 691 GGTGAGTTTGTGGTTAGTG692 TTTTCTAAAAAAATCCAATCTA 693 AATGGATAGGTTGGAATAG 694AAAAAAAAAAAAAAACTAATTAC 695 GAGTTATTTAGTTTGGTTAGGT 696ACTCAACTTAAAAAATCACTATAC 697 TTTTTTTTGGTTTTTTGGTTTT 698TCCCCCACACCCATATAA 699 TTAAAAAAAAGTATAATGAGTAGGA 700 CCCACAAAAACTCTCTACA701 AAAGGAGGTTGAGTTAGAAAGTAG 702 AACTATTTAACTTACTTAACCACACC 703GGTGTGGTTAAGTAAGTTAAATAGT 704 TACCCCTTCCTCTTCAAC 705TTTTGATATGATTTATGATTATAT 706 TTTTCCACTAAACAACACTA 707TTTGAGGGTTGTTTTAGAT 708 ACTCACAAAAAATAACTAATAACTAT 709AAAGGAGGTAGGGGAGATATA 710 TCAAAATAAAAACCAAAATTCTC 711AGGTTAAGTTGGTAGAGGTAGA 712 CAAACTCTAAACTCAAAATATATTC 713TTTTTATTTTAGTTTTTTGAGTAG 714 CCCTACAACACTCCTATCTA 715TTTGGAGTTAGGTTGATAG 716 CAACAATACTCTCACTTACAC 717AGAAAGATTTTTAAATATTTTTAAT 718 AAACCTCTAATACACAACAAA 719TTTTGAGTTTTTTTTTTAAGTAT 720 CAAACAAAACAACACTTAATAC 721GGTTGAGGTGGGTGGATTA 722 TTTTTTTTTTTTTTTTTTAAAATAAAATCT 723GGGTGTTTGTAATTTTAGTT 724 ACCTTTAACAACCTAACAATATA 725GGGTAGATGATATGGTAGTGA 726 AAAAAATAAAAAATAACTAAAACAATAT 727AGGAAGTGTTTAAGAAGTAGAA 728 CCTAAAACTCTAAATACAATCTC 729TTTTTAATTTTTGTTTGTATT 730 AAACCACAATCTATTTCTAA 731TTAGAAAAGAATAATTATAGTTG 732 ACCCTAAAAAAATAAAATC 733TTGTATTAGTAAATAAAGTGTATTTT 734 AACCCTTTCTACAAATCTAC 735AGGGGTGGGTGGAAGAAT 736 CTCCTCAATAAAATAAAAATCCTAAAAAATA 737GGGTTAATTAGTTGTTTTAT 738 CCTACAAATATATCACACACT 739 TTTGTTAAATAGGTGGTTAGA740 ACCTCAACCTCCTAAATAAC 741 TAGGGTTTAGAGTAGGAGGTAG 742CAAAAAATATAAATCAAAAACATC 743 GGGATTATAGGTATTTATTAT 744TAAAAATTAAAAATCATACTTA 745 AAGTGATTTTTAGGGAGTGT 746TCCATAATAACCTCATTTTAATA 747 TTTTTGGTTGAGGTTTAGT 748AAACAACACAACTCTTATCAC 749 TATGGTGATTAAAGTATAATAGTT 750TCCTAAATAAAAAACAACATA 751 TGAAAATGTTTTTAGTTTTTATT 752AAATACCCTACCTCTTATCTAA 753 GATGGTTAATTTTTTTATTT 754 ACTCCTTCAACAAACTAAC755 AGGGGATATTTTTAGGTT 756 CCAATCTATTCCTATATAATTAA 757AGGAGAGTTTGGAAATATAG 758 CAATTCTAAATTAAACCTTATT 759AATAATGGTAGTAGTTTTATTAG 760 TTCCTATATTAACAACTTACA 761TTTTTTGGTAGATTTTTAT 762 AAATTAATTTCTATTATTTATATTA 763 AGGTGGTTGGGGAGAGTG764 CCCTAAAATAAATCAAAAAAAACCTTAA 765 AGGTTTAGGTGGGGTGAAT 766TAAAATCATCAAAATCCCTTAAAA 767 TTTTTTTTTAGGTTATAGGAGTATT 768ATCCCCACAAAACACATA 769 TAGGGTAAATATTGGGATTATT 770 TTTCCACCTCAAAACTTAAC771 GGGTGTTTGTATTTTTATATT 772 ACCTCCCAAAACCATAAC 773GATGTGAGTGGTGAGGTGGT 774 CAAACCCTTCCAAAACATAAAC 775 TGGGATTATAGGTATGTATT776 CAATTTCATTTATAAATATAAATAT 777 AGGGGTTGGTTATTTTTATTTT 778TTTTTAATATTTAATTTTTACCTTCAACT 779 GGTAAGTTGTGGATGTGAGT 780AAAAAAAACCAAACCTTATCTA 781 TTTTTAGGATTTGGGTTAG 782AACCTTATAAATAACAACAAAAC

Kit for Detecting Methylation Level of a Thyroid Nodule

Also provided is a kit including a plurality (e.g., at least about 10,20, 40, 50, 100, 150, 200, 225, or 232) nucleic acids each independentlycomprising one sequence selected from SEQ ID NO:551 to SEQ ID NO:782, inwhich the nucleic acids do not simultaneously include the same sequence.

In some aspects, the kit includes deoxyribonucleic acid that has asequence that is at least 50%-55%, 55%-60%, 60%-65%, 65%-70%, 70%-75%,75%-80%, 80%-85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% ormore identical or homologous to a nucleic acid having a sequence of atleast one of SEQ ID NO:551 to SEQ ID NO:782.

The kit provided herein may include enzymes, reagents for deamination ofcytosine, buffers, vials, plasmid vectors, control DNA, devices forcollecting thyroid tissue samples, reagents for isolating DNA, reagentsfor labeling DNA, labels, or any combinations thereof.

The kit provided herein may include enzymes such as thermostable DNApolymerase enzymes, restriction enzymes, and combination thereof.

In embodiments, the kit(s) may further include enzymes, reagents fordeamination of cytosine, buffers, vials, control DNA, devices forcollecting blood and/or tissue samples, or reagents for labeling DNA, orany combinations thereof.

In embodiments, a kit provided herein may include a solid carriercapable of adsorbing the nucleic acids containing in a sample of a bodyfluid, for example blood (whole blood, plasma, or serum). The kit mayalso contain other components for example, reagents, in concentrated orfinal dilution form, chromatographic materials for the separation of thenucleic acids, aqueous solutions (buffers, optionally also inconcentrated form for final adjusting by the user) or chromatographicmaterials for desalting nucleic acids which have been eluted with sodiumchloride.

In embodiments, a kit provided herein includes materials for purifyingnucleic acids, for example, inorganic and/or organic carriers andoptionally solutions, excipients and/or accessories. Such agents areknown and are commercially available. For solid phase nucleic acidisolation methods, many solid supports have been used including membranefilters, magnetic beads, metal oxides, and latex particles.

In addition, a kit can also contain excipients such as, for example, aprotease such as proteinase K, or enzymes and other agents formanipulating nucleic acids, e.g., at least one amplification primer,nucleic acid bases (A, T, G, C, and/or U), and enzymes suitable foramplifying nucleic acids, e.g., DNase, a nucleic acid polymerase and/orat least one restriction endonuclease. Alternatively, a commercialpolymerase chain reaction kit may be used to amplify the DNA samples.

Exemplary Techniques for Detecting Specific Sequences

Specific sequences, such as the sequences listed in Table 1 (or portionsthereof containing a methylation site of interest), can be detected bynumerous methods that are well-established in the art (e.g., PCR-basedsequence specific amplification, isozyme markers, northern analysis,sequence specific hybridization, and array based hybridization). Inembodiments, the presence or absence of methylation is determinedthrough nucleotide sequencing of the site of interest (e.g., the site inbisulfite-treated DNA or an amplicon thereof). Any of these methods arereadily adapted to high throughput analysis.

Some techniques for detecting specific sequences utilize hybridizationof a probe nucleic acid to nucleic acids corresponding to themethylation site of interest (e.g., amplified nucleic acids producedusing bisulfite-treated DNA as a template or the bisulfite-treated DNAitself). Hybridization formats, including, but not limited to: solutionphase, solid phase, mixed phase, or in situ hybridization assays areuseful for sequence detection. A non-limiting guide to the hybridizationof nucleic acids is found in Tijssen (1993) Laboratory Techniques inBiochemistry and Molecular Biology--Hybridization with Nucleic AcidProbes Elsevier, N.Y., as well as in Sambrook, Berger and Ausubel.

Nucleic acid probes complementary to a methylation site can be clonedand/or synthesized. Any suitable label can be used with a probe.Detectable labels suitable for use with nucleic acid probes include, forexample, any composition detectable by spectroscopic, radioisotopic,photochemical, biochemical, immunochemical, electrical, optical orchemical means. Useful labels include biotin for staining with labeledstreptavidin conjugate, magnetic beads, fluorescent dyes, radiolabels,enzymes, and colorimetric labels. Other labels include ligands whichbind to antibodies labeled with fluorophores, chemiluminescent agents,and enzymes. A probe can also constitute radiolabelled PCR primers thatare used to generate a radiolabelled amplicon. Labeling strategies forlabeling nucleic acids and corresponding detection strategies can befound, e.g., in Haugland (2003) Handbook of Probes and ResearchChemicals Ninth Edition by Molecular Probes, Inc. (Eugene Oreg.).Additional non-limiting details regarding sequence detection strategiesare found below.

PCR, RT-PCR and LCR are in particularly broad use as amplification andamplification-detection methods for amplifying nucleic acids (e.g.,those comprising a methylation site), facilitating detection of thenucleic acids of interest.

In embodiments, real time PCR or LCR is performed on the amplificationmixtures described herein, e.g., using molecular beacons or TaqMan™probes. A molecular beacon (MB) is an oligonucleotide or peptide nucleicacid (PNA) which, under appropriate hybridization conditions,self-hybridizes to form a stem and loop structure. The MB has a labeland a quencher at the termini of the oligonucleotide or PNA; thus, underconditions that permit intra-molecular hybridization, the label istypically quenched (or at least altered in its fluorescence) by thequencher. Under conditions where the MB does not display intra-molecularhybridization (e.g., when bound to a target nucleic acid, e.g., to aregion of an amplicon during amplification), the MB label is unquenched.Details regarding standard methods of making and using MBs are wellestablished in the literature and MBs are available from a number ofcommercial reagent sources. See also, e.g., Leone et al. (1995)“Molecular beacon probes combined with amplification by NASBA enablehomogenous real-time detection of RNA.” Nucleic Acids Res. 26:2150-2155;Tyagi and Kramer (1996) “Molecular beacons: probes that fluoresce uponhybridization” Nature Biotechnology 14:303-308; Blok and Kramer (1997)“Amplifiable hybridization probes containing a molecular switch” MolCell Probes 11:187-194; Hsuih et al. (1997) “Novel, ligation-dependentPCR assay for detection of hepatitis C in serum” J Clin Microbiol34:501-507; Kostrikis et al. (1998) “Molecular beacons: spectralgenotyping of human alleles” Science 279:1228-1229; Sokol et al. (1998)“Real time detection of DNA:RNA hybridization in living cells” Proc.Natl. Acad. Sci. U.S.A. 95:11538-11543; Tyagi et al. (1998) “Multicolormolecular beacons for allele discrimination” Nature Biotechnology16:49-53; Bonnet et al. (1999) “Thermodynamic basis of the chemicalspecificity of structured DNA probes” Proc. Natl. Acad. Sci. U.S.A.96:6171-6176; Fang et al. (1999) “Designing a novel molecular beacon forsurface-immobilized DNA hybridization studies” J. Am. Chem. Soc.121:2921-2922; Marras et al. (1999) “Multiplex detection ofsingle-nucleotide variation using molecular beacons” Genet. Anal.Biomol. Eng. 14:151-156; and Vet et al. (1999) “Multiplex detection offour pathogenic retroviruses using molecular beacons” Proc. Natl. Acad.Sci. U.S.A. 96:6394-6399. Additional details regarding MB constructionand use is found in the patent literature, e.g., U.S. Pat. No. 5,925,517(Jul. 20, 1999) to Tyagi et al. entitled “Detectably labeled dualconformation oligonucleotide probes, assays and kits;” U.S. Pat. No.6,150,097 to Tyagi et al (Nov. 21, 2000) entitled “Nucleic aciddetection probes having non-FRET fluorescence quenching and kits andassays including such probes” and U.S. Pat. No. 6,037,130 to Tyagi et al(Mar. 14, 2000), entitled “Wavelength-shifting probes and primers andtheir use in assays and kits.”

PCR detection and quantification using dual-labeled fluorogenicoligonucleotide probes, commonly referred to as “TaqMan™” probes, canalso be performed. These probes are composed of short (e.g., 20-25 base)oligodeoxynucleotides that are labeled with two different fluorescentdyes. On the 5′ terminus of each probe is a reporter dye, and on the 3′terminus of each probe a quenching dye is found. The oligonucleotideprobe sequence is complementary to an internal target sequence presentin a PCR amplicon. When the probe is intact, energy transfer occursbetween the two fluorophores and emission from the reporter is quenchedby the quencher by FRET. During the extension phase of PCR, the probe iscleaved by 5′ nuclease activity of the polymerase used in the reaction,thereby releasing the reporter from the oligonucleotide-quencher andproducing an increase in reporter emission intensity. Accordingly,TaqMan™ probes are oligonucleotides that have a label and a quencher,where the label is released during amplification by the exonucleaseaction of the polymerase used in amplification. This provides a realtime measure of amplification during synthesis. A variety of TaqMan™reagents are commercially available, e.g., from Applied Biosystems(Division Headquarters in Foster City, Calif.) as well as from a varietyof specialty vendors such as Biosearch Technologies (e.g., black holequencher probes). Further details regarding dual-label probe strategiescan be found, e.g., in WO92/02638.

Other similar methods include e.g. fluorescence resonance energytransfer between two adjacently hybridized probes, e.g., using the“LightCycler™” format described in U.S. Pat. No. 6,174,670.

Amplification and Sequencing Primers

In embodiments, methylation sites are detected using primers, e.g., toamplify and/or sequence polynucleotides comprising the methylationsites.

Suitable primers can be designed and is not intended that the presentsubject matter be limited to any particular primer or primer pair. Forexample, primers can be designed using any suitable software program,such as LASERGENE™, e.g., taking account of publicly available sequenceinformation. Flanking sequences for the methylation sites identifiedherein are publicly available; accordingly, suitable amplificationprimers can be constructed based on well understood base-pairing rules.The sequence of any amplicon can be detected as has already beendiscussed above, e.g., by sequencing, hybridization, arrayhybridization, PCR, LCR, or the like.

In embodiments, the primers are radiolabelled, or labeled by anysuitable means (e.g., using a non-radioactive fluorescent tag), to allowfor rapid visualization of differently sized amplicons following anamplification reaction without any additional labeling step orvisualization step. In embodiments, the primers are not labeled, and theamplicons are visualized following their size resolution, e.g.,following agarose or acrylamide gel electrophoresis. In embodiments,ethidium bromide staining of the PCR amplicons following size resolutionallows visualization of the different size amplicons.

It is not intended that the primers be limited to generating an ampliconof any particular size. The primers can generate an amplicon of anysuitable length for detection (e.g., by sequencing or hybridization). Inembodiments, amplification produces an amplicon at least 20 nucleotidesin length, or alternatively, at least 50 nucleotides in length, oralternatively, at least 100 nucleotides in length, or alternatively, atleast 200 nucleotides in length. Amplicons of any size can be detectedand/or sequenced using various technologies described herein and knownin the art.

Detection of Methylation Levels Using Sequencing

Sequencing is the process of determining the precise order ofnucleotides within a DNA molecule. The advent of rapid DNA sequencingmethods has greatly accelerated biological and medical research anddiscovery. Non-limiting examples and descriptions are provided below.However, embodiments are not limited to the use of a particularsequencing assay, technology, or approach.

Sanger sequencing is a method of DNA sequencing based on the selectiveincorporation of chain-terminating dideoxynucleotides by DNA polymeraseduring in vitro DNA replication (Sanger F; Coulson AR (May 1975) J. Mol.Biol. 94 (3): 441-8; Sanger et al. (December 1977) Proc. Natl. Acad.Sci. U.S.A. 74 (12): 5463-7).

In embodiments, next-generation sequencing is used. Non-limitingexamples of next-generation sequencing methods include massivelyparallel signature sequencing (MPSS), single-molecule real-timesequencing, ion semiconductor sequencing, pyrosequencing, sequencing bysynthesis, sequencing by ligation, chain termination, DNA nanoballsequencing, helicos single molecule sequencing, single molecule realtime sequencing, nanopore DNA sequencing, tunnelling currents DNAsequencing, and sequencing by hybridization.

Many commercially available sequencing technologies, devices, andservices are available. In embodiments, an Illumina sequencer is used.In embodiments, PCR products are ligated with a linker and sequencedusing a high throughput sequencer, such as an Illumina sequencer. Inembodiments, the ligation step can be avoided, omitted, or eliminated byadding a linker to amplification primers.

Array-Based Sequence Detection

Array-based detection can be performed using commercially availablearrays, e.g., from Affymetrix (Santa Clara, Calif.) or othermanufacturers. Reviews regarding the operation of nucleic acid arraysinclude Sapolsky et al. (1999) “High-throughput polymorphism screeningand genotyping with high-density oligonucleotide arrays.” GeneticAnalysis: Biomolecular Engineering 14:187-192; Lockhart (1998) “Mutantyeast on drugs” Nature Medicine 4:1235-1236; Fodor (1997) “Genes, Chipsand the Human Genome.” FASEB Journal 11:A879; Fodor (1997) “MassivelyParallel Genomics.” Science 277: 393-395; and Chee et al. (1996)“Accessing Genetic Information with High-Density DNA Arrays.” Science274:610-614.

A variety of probe arrays have been described in the literature and canbe used for detection of methylation. For example, DNA probe array chipsor larger DNA probe array wafers (from which individual chips wouldotherwise be obtained by breaking up the wafer) may be used inembodiments described herein. DNA probe array wafers generally compriseglass wafers on which high density arrays of DNA probes (short segmentsof DNA) have been placed. Each of these wafers can hold, for example,approximately 60 million DNA probes that are used to recognize longersample DNA sequences (e.g., from individuals or populations, e.g., thatcomprise methylation sites of interest). The recognition of sample DNAby the set of DNA probes on the glass wafer takes place through DNAhybridization. When a DNA sample hybridizes with an array of DNA probes,the sample binds to those probes that are complementary to the sampleDNA sequence. By evaluating to which probes the sample DNA for anindividual hybridizes more strongly, it is possible to determine whethera known sequence of nucleic acid is present or not in the sample,thereby determining whether a uracil, thymine, or cytosine is present ata polynucleotide site corresponding to a genomic methylation site. Onecan also use this approach to control the hybridization conditions topermit single nucleotide discrimination, e.g., for the identification ofmethylation at a site of interest. Arrays provide one convenientembodiment for detecting multiple methylation sites simultaneously (orin series). Of course, any detection technology (PCR, LCR, and/orsequencing etc.) can similarly be used, e.g., with multiplexamplification/detection/sequencing reactions, or simply by runningseveral separate reactions, e.g., simultaneously or in series.

In embodiments, the use of DNA probe arrays to obtain methylationinformation involves the following general steps: design and manufactureof DNA probe arrays, preparation of the sample, bisulfite treatment,hybridization of sample DNA to the array, detection of hybridizationevents and data analysis to determine sequence. In embodiments, an arrayis used to capture polynucleotides containing a methylation site ofinterest, and the captured polynucleotides are subsequently amplifiedand/or sequenced. Preferred wafers are manufactured using a processadapted from semiconductor manufacturing to achieve cost effectivenessand high quality, and are available, e.g., from Affymetrix, Inc. ofSanta Clara, Calif.

For example, probe arrays can be manufactured by light-directed chemicalsynthesis processes, which combine solid-phase chemical synthesis withphotolithographic fabrication techniques as employed in thesemiconductor industry. Using a series of photolithographic masks todefine chip exposure sites, followed by specific chemical synthesissteps, the process constructs high-density arrays of oligonucleotides,with each probe in a predefined position in the array. Multiple probearrays can be synthesized simultaneously on a large glass wafer. Thisparallel process enhances reproducibility and helps achieve economies ofscale.

In embodiments, DNA probe arrays can be used to obtain data regardingpresence of sequences (e.g., corresponding to methylated or unmethylatedDNA) of interest. The DNA samples may be tagged with biotin and/or afluorescent reporter group by standard biochemical methods. The labeledsamples are incubated with an array, and segments of the samples bind,or hybridize, with complementary sequences on the array. The array canbe washed and/or stained to produce a hybridization pattern. The arrayis then scanned and the patterns of hybridization are detected byemission of light from the fluorescent reporter groups. Because theidentity and position of each probe on the array is known, the nature ofthe DNA sequences in the sample applied to the array can be determined.

In embodiments, the nucleic acid sample to be analyzed is isolated,bisulfite-treated, amplified and, optionally, labeled with biotin and/ora fluorescent reporter group. The labeled nucleic acid sample may thenincubated with the array using a fluidics station and hybridizationoven. The array can be washed and or stained or counter-stained, asappropriate to the detection method. After hybridization, washing andstaining, the array is inserted into a scanner, where patterns ofhybridization are detected. The hybridization data are collected aslight emitted from the fluorescent reporter groups already incorporatedinto the labeled nucleic acid, which is now bound to the probe array.Probes that most clearly match the labeled nucleic acid produce strongersignals than those that have mismatches. Since the sequence and positionof each probe on the array are known, by complementarity, the identityof the nucleic acid sample applied to the probe array can be identified.In embodiments, hybridization techniques and conditions that allow onlyfully complementary nucleotide sequences to hybridize with probes in anarray are used.

Prior to amplification and/or detection of a nucleic acid comprising asequence of interest, the nucleic acid is optionally purified from thesamples by any available method, e.g., those taught in Berger andKimmel, Guide to Molecular Cloning Techniques, Methods in Enzymologyvolume 152 Academic Press, Inc., San Diego, Calif. (Berger); Sambrook etal., Molecular Cloning--A Laboratory Manual (3rd Ed.), Vol. 1-3, ColdSpring Harbor Laboratory, Cold Spring Harbor, N.Y., 2001 (“Sambrook”);and/or Current Protocols in Molecular Biology, F. M. Ausubel et al.,eds., Current Protocols, a joint venture between Greene PublishingAssociates, Inc. and John Wiley & Sons, Inc., (supplemented through2002) (“Ausubel”)). A plethora of kits are also commercially availablefor the purification of nucleic acids from cells or other samples (see,e.g., EasyPrep.TM., FlexiPrep.TM., both from Pharmacia Biotech;StrataClean.TM., from Stratagene; and, QIAprep.TM. from Qiagen).Alternately, samples can simply be directly subjected to amplificationor detection, e.g., following aliquotting and/or dilution.

Thyroid Cancer Diagnostic System and Processes

FIG. 4 depicts a block diagram illustrating an exemplary thyroid cancerdiagnostic system 600. Referring to FIG. 4 , the thyroid cancerdiagnostic system 600 can include an input module 610, an isolationmodule 612, a conversion module 614, a detection module 616, a diagnosismodule 618, a treatment module 620, and a user interface (UI) module622. The thyroid cancer diagnostic system 600 can be configured toprovide a diagnosis indicative of a presence of thyroid cancer and/or arisk of developing thyroid cancer. Moreover, the thyroid cancerdiagnostic system 600 can be further configured to generate a treatmentplan for a subject based on the diagnosis. For instance, when thediagnosis indicates a presence and/or risk of thyroid cancer in asubject, the thyroid cancer diagnostic system 600 can recommend one ormore treatments including, for example, thyroid surgery, radiationtherapy, radioactive iodine therapy, chemotherapy, thyroid hormonetherapy, and administration of an active agent.

One or more modules of the thyroid cancer diagnostic system 600 can berealized in digital electronic circuitry, integrated circuitry,specially designed application specific integrated circuits (ASICs),field programmable gate arrays (FPGAs) computer hardware, firmware,software, and/or combinations thereof. The thyroid cancer diagnosticsystem 600 can further be communicatively coupled with one or moredevices including, for example, a device 630. The thyroid cancerdiagnostic system 600 can communicate with the device 620 via a wiredand/or wireless network 640 (e.g., a wide area network (WAN), a localarea network (LAN), and/or the Internet). As shown in FIG. 4 , thethyroid cancer diagnostic system 600 can be further coupled with a datastore 650.

The input module 610 can be adapted to receive and/or collect a sampleof a thyroid nodule obtained from a subject. The isolation module 612can be configured to isolate DNA from the thyroid nodule sample receivedby the input module 610 thereby forming isolated thyroid nodule DNA. Theconversion module 614 can be configured to treat the isolated thyroidnodule DNA including by contacting the isolated thyroid nodule DNA withone or more bisulfite reagents including, for example, a bisulfite salt.Exposing the isolated thyroid nodule DNA to one or more bisulfitereagents can convert cytosine to uracil while 5-mC is left unmodified.Thus, the 5-mC present in the isolated thyroid nodule DNA will remain inthe reacted thyroid nodule DNA. Meanwhile, any cytosine in the isolatedthyroid nodule DNA will be replaced by uracil in the reacted thyroidnodule DNA. In embodiments, the treatment of the isolated thyroid noduleDNA can be performed by applying one or more kits (e.g., the BisulflashDNA Modification Kit (Epigentek) or Imprint DNA Modification Kit(Sigma)).

In embodiments, the conversion module 614 can be further adapted toensure optimal bisulfite conversion (e.g., with desired DNA fragmentsize for post-bisulfite ligation) by controlling one or more of aconcentration of the bisulfite reagents, temperature, and reaction timeperiod. It should be appreciated that the conversion module 614 can beadapted to use a different and/or additional type of reagent withoutdeparting from the scope of the present subject matter. For example, theconversion module 614 can treat the isolated thyroid nodule DNA withpotassium chloride, which may reduce the thermophilic DNA degradationassociated with the conversion of cytosine to uracil. Moreover, theconversion module 614 can be configured to perform additional processingof the reacted thyroid nodule DNA including, for example, desulphonation(e.g., with an alkalized solution), cleansing (e.g., by elution), andamplification (e.g., using the PCR method).

The detection module 616 can be configured to detect a methylationand/or unmethylation of the thyroid nodule DNA. For instance, thedetection module 616 can detect methylation by detecting a presence ofuracil in the reacted thyroid nodule DNA generated by the conversionmodule 614. Alternately and/or additionally, the detection module 616can detect unmethylation by detecting an absence of uracil in thereacted thyroid nodule DNA. In embodiments, the detection module 616 canbe configured detect the presence and/or absence of uracil at specificmethylation sites. That is, the detection module 616 can be configuredto detect the presence and/or absence of uracil at specific chromosomalpositions of certain chromosomes. For example, the thyroid cancerdiagnostic system 600 can store a plurality of specific methylationsites (e.g., Table 1) in the data store 650. As such, to detectmethylation, the detection module 616 can be configured to obtain, fromthe data store 650, one or more specific methylation sites at which totest for the presence and/or absence of uracil. Moreover, inembodiments, the detection module 616 can be configured to determine alevel of methylation and/or unmethylation at the specific methylationsites. The level of methylation at a particular site can correspond to aproportion of the reacted thyroid nodule DNA that has a cytosine ratherthan a uracil at that site. By contrast, the level of unmethylation at aparticular site can correspond to a proportion of reacted thyroid noduleDNA that has a uracil rather than a cytosine at that site.

In embodiments, the conversion module 614 may amplify the reactedthyroid nodule DNA such as by using a PCR method. The detection ofmethylation and/or unmethylation in amplified reacted thyroid nodule DNAmay require detection of a presence and/or absence of thymidine at asite of interest in amplicons amplified from the reacted thyroid noduleDNA. That is, instead of detecting the presence and/or absence ofuracil, the detection module 616 can be configured to detect methylationand/or unmethylation of amplified reacted thyroid nodule DNA bydetecting a presence and/or absence of thymidine at specific methylationsites (e.g., as set forth in Table 1).

The diagnosis module 618 can be configured to generate a diagnosis forthe subject based on whether the detection module 616 detectsmethylation and/or unmethylation at the plurality of specificmethylation sites (e.g., Table 1). Alternately or additionally, thediagnosis module 618 can be configured to generate a diagnosis for thesubject based on a level of methylation and/or unmethylation detected bythe detection module 616 at the plurality of specific methylation sites.For instance, diagnosis module 618 can determine that the thyroid noduleis malignant (e.g., cancerous) when the unmethylation level (e.g.,proportion of uracil) at different methylation sites exceeds thecorresponding thresholds (e.g., as set forth in Table 2). Inembodiments, the diagnosis module 618 can further generate a diagnosisfor the subject based on one or more of the subject’s PTC methylationalternation score, a BTN methylation alternation score, and/or aComposite Cancer Risk Score.

In embodiments, the diagnosis module 618 can be configured to determinea PTC methylation alternation score for the subject. In embodiments, thePTC methylation alteration score can correspond to a number of specificmethylation sites (e.g., as set forth in Table 1) that have a uracillevel (or corresponding thymidine level if amplicons are being analyzed)equal to or greater than the corresponding thresholds (e.g., as setforth in Table 2). Alternately or additionally, the diagnosis module 618can be configured to determine a BTN methylation alternation score forthe subject. The BTN methylation alteration score can correspond to anumber of specific methylation sites (e.g., as set forth in Table 1)that have a uracil level (or corresponding thymidine level if ampliconsare being analyzed) equal to or greater than the various correspondingthreshold level (e.g., as set forth in Table 3 and/or Table 4).

In embodiments, the diagnosis module 618 can further be configured tocompute a Composite Cancer Risk Score for the subject. The diagnosismodule 618 can compute the Composite Cancer Risk Score based on the PTCmethylation alteration score and the BTN methylation alteration scorefor the subject. For example, the Composite Cancer Risk Score for thesubject can be computed based on equation (1):

$\frac{\left\lbrack \text{the PTC methylation alteration score for the subject} \right\rbrack}{\left\lbrack \text{BTN methylation alteration score for the subject} \right\rbrack.}$

Alternately or additionally, the Composite Cancer Risk Score for thesubject can be computed based on equation (2):

$\frac{\left\lbrack {\left( \text{the PTC methylation alteration score for the subject} \right) + 1} \right\rbrack}{\left\lbrack {\left( \text{BTN methylation alteration score for the subject} \right) + 1} \right\rbrack}$

The treatment module 620 can be configured to formulate a treatment planfor the subject based on the diagnosis generated by the diagnosis module618. For instance, when the diagnosis generated by the diagnosis module618 indicates a presence and/or risk of a malignant (e.g., cancerous)thyroid nodule, the treatment module 620 can prescribe one or moretreatments including, for example, thyroid surgery, radiation therapy,radioactive iodine therapy, chemotherapy, thyroid hormone therapy, andadministration of an active agent. In embodiments, the treatment module620 can be configured to provide the treatment plan to the device 630via the network 640. Alternately or additionally, the treatment module620 can store the treatment plan in the data store 650.

The UI module 622 can be configured to generate a UI through which auser (e.g., a physician) can interface with the thyroid cancerdiagnostic system 600. For example, the UI module 622 can provide one ormore graphic user interfaces (GUIs) configured to display the diagnosisand/or treatment plan for the subject.

FIG. 5 depicts a flowchart illustrating an exemplary process 700 fordiagnosing thyroid cancer. Referring to FIGS. 4-5 , the process 700 canbe performed by the thyroid cancer diagnostic system 600.

The thyroid cancer diagnostic system 600 (e.g., the input module 610)can receive a sample of a thyroid nodule from a subject (702). Thethyroid cancer diagnostic system 600 (e.g., the isolation module 612)can isolate thyroid nodule DNA from the thyroid nodule sample (704). Thethyroid cancer diagnostic system 600 (e.g., the conversion module 614)can treat the isolated thyroid nodule DNA with a bisulfite salt togenerate reacted thyroid nodule DNA (706). Treating the isolated thyroidnodule DNA with the bisulfite salt can form a reacted thyroid nodule DNAby converting the cytosine present in the isolated thyroid nodule DNA touracil. In embodiments, the thyroid cancer diagnostic system 600 canfurther process the reacted thyroid nodule DNA by desulphonating,cleansing, and/or amplifying the reacted thyroid nodule DNA.

The thyroid cancer diagnostic system 600 (e.g., the detection module616) can detect methylation and/or unmethylation of the isolated thyroidnodule DNA by at least detecting a presence and/or absence of uracil inthe reacted thyroid nodule DNA (708). In embodiments, the thyroid cancerdiagnostic system 600 can be configured to detect a presence and/orabsence of uracil at specific methylation sites (e.g., as set forth inTable 1). Moreover, the thyroid cancer diagnostic system 600 can beconfigured to detect a level of methylation and/or unmethylation at themethylation sites.

The thyroid cancer diagnostic system 600 (e.g., the diagnostics module618) can generate a diagnosis for the subject based on the methylationand/or unmethylation of the isolated thyroid nodule DNA (710). Forexample, the thyroid cancer diagnostic system 600 can generate adiagnosis based on a level of methylation and/or unmethylation at aplurality of specific methylation sites. Each methylation site may beassociated with a certain threshold unmethylation level (e.g., as setforth in Table 2). As such, the thyroid cancer diagnostic system 600 candetermine that the thyroid nodule from the subject is malignant (e.g.,cancerous) if the level of unmethylation at the plurality of methylationsites exceeds the corresponding thresholds.

The thyroid cancer diagnostic system 600 (e.g., the treatment module620) can formulate, based on the diagnosis, a treatment plan for thesubject (712). For example, when the diagnosis indicates that a presenceand/or risk of malignant thyroid nodules in the subject, the thyroidcancer diagnostic system 600 can prescribe thyroid surgery, radiationtherapy, radioactive iodine therapy, chemotherapy, thyroid hormonetherapy, and/or administration of an active agent. The thyroid cancerdiagnostic system 600 (e.g., the UI module 622) can provide, via a UI(e.g., GUI at the device 630), the diagnosis and/or the treatment planfor the subject (714).

FIG. 6 depicts a flowchart illustrating an exemplary process 800 fordiagnosing thyroid cancer. Referring to FIGS. 4 and 6 , the process 700can be performed by the thyroid cancer diagnostic system 600.

The thyroid cancer diagnostic system 600 (e.g., the input module 610)can receive a sample of a thyroid nodule from a subject (802). Thethyroid cancer diagnostic system 600 (e.g., the isolation module 612)can isolate thyroid nodule DNA from the thyroid nodule sample (804). Thethyroid cancer diagnostic system 600 (e.g., the conversion module 614)can treat the isolated thyroid nodule DNA with a bisulfite salt togenerate reacted thyroid nodule DNA (806).

As shown in FIG. 6 , the thyroid cancer diagnostic system 600 (e.g., theconversion module 614) can amplify the reacted thyroid nodule DNA (808).For instance, the thyroid cancer diagnostic system 600 can amplify thereacted thyroid nodule DNA subsequent to treating the isolated thyroidnodule NA with the bisulfite salt to generate the reacted thyroid noduleDNA. The thyroid cancer diagnostic system 600 can detect methylationand/or unmethylation of the isolated thyroid nodule DNA by detecting apresence and/or absence of thymidine in the amplified reacted thyroidnodule DNA (810).

The thyroid cancer diagnostic system 600 (e.g., the diagnostics module618) can generate a diagnosis for the subject based on the methylationand/or unmethylation of the isolated thyroid nodule DNA (812). Moreover,the thyroid cancer diagnostic system 600 (e.g., the treatment module620) can formulate, based on the diagnosis, a treatment plan for thesubject (814). The thyroid cancer diagnostic system 600 (e.g., the UImodule 622) can provide, via a UI, the diagnosis and/or treatment planfor the subject.

It should be appreciated that the process 700 and/or 800 can includedifferent and/or additional operations without departing from the scopeof the present subject matter. Moreover, one or more operations of theprocess 700 and/or 800 can be omitted and/or repeated without departingfrom the scope of the present subject matter.

Implementations of the present subject matter can include, but are notlimited to, methods consistent with the descriptions provided above aswell as articles that comprise a tangibly embodied machine-readablemedium operable to cause one or more machines (e.g., computers, etc.) toresult in operations implementing one or more of the described features.Similarly, computer systems are also described that can include one ormore processors and one or more memories coupled to the one or moreprocessors. A memory, which can include a computer-readable storagemedium, can include, encode, store, or the like one or more programsthat cause one or more processors to perform one or more of theoperations described herein. Computer implemented methods consistentwith one or more implementations of the current subject matter can beimplemented by one or more data processors residing in a singlecomputing system or multiple computing systems. Such multiple computingsystems can be connected and can exchange data and/or commands or otherinstructions or the like via one or more connections, including but notlimited to a connection over a network (e.g. the Internet, a wirelesswide area network, a local area network, a wide area network, a wirednetwork, or the like), via a direct connection between one or more ofthe multiple computing systems, etc.

One or more aspects or features of the subject matter described hereincan be realized in digital electronic circuitry, integrated circuitry,specially designed ASICs, FPGAs, computer hardware, firmware, software,and/or combinations thereof. These various aspects or features caninclude implementation in one or more computer programs that areexecutable and/or interpretable on a programmable system including atleast one programmable processor, which can be special or generalpurpose, coupled to receive data and instructions from, and to transmitdata and instructions to, a storage system, at least one input device,and at least one output device. The programmable system or computingsystem can include clients and servers. A client and server aregenerally remote from each other and typically interact through acommunication network. The relationship of client and server arises byvirtue of computer programs running on the respective computers andhaving a client-server relationship to each other.

These computer programs, which can also be referred to programs,software, software applications, applications, components, or code,include machine instructions for a programmable processor, and can beimplemented in a high-level procedural language, an object-orientedprogramming language, a functional programming language, a logicalprogramming language, and/or in assembly/machine language. As usedherein, the term “machine-readable medium” refers to any computerprogram product, apparatus and/or device, such as for example magneticdiscs, optical disks, memory, and Programmable Logic Devices (PLDs),used to provide machine instructions and/or data to a programmableprocessor, including a machine-readable medium that receives machineinstructions as a machine-readable signal. The term “machine-readablesignal” refers to any signal used to provide machine instructions and/ordata to a programmable processor. The machine-readable medium can storesuch machine instructions non-transitorily, such as for example as woulda non-transient solid-state memory or a magnetic hard drive or anyequivalent storage medium. The machine-readable medium can alternativelyor additionally store such machine instructions in a transient manner,such as for example as would a processor cache or other random accessmemory associated with one or more physical processor cores.

To provide for interaction with a user, one or more aspects or featuresof the subject matter described herein can be implemented on a computerhaving a display device, such as for example a cathode ray tube (CRT) ora liquid crystal display (LCD) or a light emitting diode (LED) monitorfor displaying information to the user and a keyboard and a pointingdevice, such as for example a mouse or a trackball, by which the usermay provide input to the computer. Other kinds of devices can be used toprovide for interaction with a user as well. For example, feedbackprovided to the user can be any form of sensory feedback, such as forexample visual feedback, auditory feedback, or tactile feedback; andinput from the user can be received in any form, including, but notlimited to, acoustic, speech, or tactile input. Other possible inputdevices include, but are not limited to, touch screens or othertouch-sensitive devices such as single or multi-point resistive orcapacitive trackpads, voice recognition hardware and software, opticalscanners, optical pointers, digital MRI image capture devices andassociated interpretation software, and the like.

Examples are provided below to facilitate a more complete understandingof the invention. The following examples illustrate the exemplary modesof making and practicing the invention. However, the scope of theinvention is not limited to specific embodiments disclosed in theseExamples, which are for purposes of illustration only, since alternativemethods can be utilized to obtain similar results.

EMBODIMENTS

Embodiments include embodiments P1 to P41 following.

Embodiment P1. A method of detecting methylation or unmethylation of athyroid nodule DNA of a subject, the method comprising: (i) isolatingDNA from a thyroid nodule of said subject thereby forming isolatedthyroid nodule DNA, (ii) contacting said isolated thyroid nodule DNAwith sodium bisulfite thereby forming a reacted thyroid nodule DNA,(iii) detecting the presence or absence of uracil in said reactedthyroid nodule DNA at a methylation site set forth in Table 1, therebydetecting methylation or unmethylation of said thyroid nodule DNA ofsaid subject.

Embodiment P2. The method of embodiment P1, further comprisingdetermining alteration in methylation at a plurality of methylationsites set forth in Table 1.

Embodiment P3. The method of embodiment P2, said alteration comprisesincrease or loss of uracil level at said plurality of methylation sites.

Embodiment P4. The method of embodiment P3, wherein said uracil level isabove a threshold as set forth in Table 2.

Embodiment P5. The method of embodiment P3, wherein said uracil level isabove a threshold as set forth in Table 3.

Embodiment P6. The method of embodiment P3, wherein said uracil level isbelow a threshold as set forth in Table 4.

Embodiment P7. The method of embodiment P3, wherein said subject is acandidate thyroid cancer patient.

Embodiment P8. The method of embodiment P4, wherein said above thresholdidentifies said thyroid nodule as a cancerous thyroid nodule.

Embodiment P9. The method of embodiment P5, wherein said above thresholdidentifies said thyroid nodule as a benign thyroid nodule.

Embodiment P10. The method of embodiment P6, wherein said belowthreshold identifies said thyroid nodule as a benign thyroid nodule.

Embodiment P11. The method of one of the above embodiments, wherein saidthyroid nodule is a specimen obtained by biopsy or by surgical resectionof said subject.

Embodiment P12. The method of embodiment P11, wherein said subject hasundergone thyroid surgery, radiation therapy, radioactive iodinetherapy, chemotherapy, thyroid hormone therapy, and administration of anactive agent.

Embodiment P13. The method of embodiment P12, wherein said active agentis chosen from Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq(Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate,Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate), SorafenibTosylate, and Vandetanib.

Embodiment P14. A method of determining a thyroid cancer or risk ofdeveloping thyroid cancer in a subject in need thereof, said methodcomprising: (i) isolating DNA from a thyroid nodule of said subjectthereby forming isolated thyroid nodule DNA; (ii) contacting saidisolated thyroid nodule DNA with sodium bisulfite thereby forming areacted thyroid nodule DNA; and (iii) detecting the presence or absenceof uracil in said reacted thyroid nodule DNA at a methylation site setforth in Table 1; thereby determining said thyroid cancer in saidsubject.

Embodiment P15. The method of embodiment P14, further comprisingselecting a subject that has or is at risk for developing thyroidcancer.

Embodiment P16. The method of embodiment P14, further comprisingdetermining alteration in methylation at a plurality of methylationsites set forth in Table 1.

Embodiment P17. The method of embodiment P16, said alteration comprisesincrease or loss of uracil level at said plurality of methylation sites.

Embodiment P18. The method of embodiment P17, wherein said uracil levelis above a threshold as set forth in Table 2.

Embodiment P19. The method of embodiment P17, wherein said uracil levelis above a threshold as set forth in Table 3.

Embodiment P20. The method of embodiment P17, wherein said uracil levelis below a threshold as set forth in Table 4.

Embodiment P21. The method of embodiment P17, wherein said subject is acandidate thyroid cancer patient.

Embodiment P22. The method of embodiment P18, wherein said abovethreshold identifies said thyroid nodule as a cancerous thyroid nodule.

Embodiment P23. The method embodiment P19, wherein said above thresholdidentifies said thyroid nodule as a benign thyroid nodule.

Embodiment P24. The method of embodiment P20, wherein said belowthreshold identifies said thyroid nodule as a benign thyroid nodule.

Embodiment P25. The method of embodiments P14-P24, wherein said thyroidnodule is a specimen obtained by biopsy or by surgical resection of saidsubject.

Embodiment P26. The method of embodiment P25, wherein said subject hasundergone thyroid surgery, radiation therapy, radioactive iodinetherapy, chemotherapy, thyroid hormone therapy, and administration of anactive agent, before said determination.

Embodiment P27. The method of embodiment P26, wherein said active agentis chosen from Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq(Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate,Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate), SorafenibTosylate, and Vandetanib.

Embodiment P28. A method of treating thyroid cancer in a subjectdetermined by the method as set forth in embodiment P22, comprisingadministering to said subject an active agent for treating thyroidcancer.

Embodiment P29. The method of embodiment P28, wherein said subject hasundergone surgery, radiation therapy, radioactive iodine therapy,chemotherapy, or thyroid hormone therapy, before said detection ofembodiment 14 at (iii).

Embodiment P30. The method of embodiment P29, wherein said active agentis chosen from Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq(Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate,Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate), SorafenibTosylate, and Vandetanib.

Embodiment P31. The method of one of above embodiments, wherein saidsubject has or is at risk of papillary thyroid cancer, follicularthyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer.

Embodiment P32. A deoxyribonucleic acid 5 to 100 nucleotides in lengthcomprising a uracil-containing sequence identical to at least a 5contiguous nucleotide sequence within a sequence chosen from SEQ ID NO:1to SEQ ID NO:550.

Embodiment P33. The deoxyribonucleic acid of embodiment P32 identical to5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100,100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180,180-190, or 190-200 of contiguous nucleotide sequence of said sequencechosen from SEQ ID NO:1 to SEQ ID NO:550.

Embodiment P34. The deoxyribonucleic acid of embodiment P32 or P33,wherein said sequence comprises a methylation site set forth in Table 2.

Embodiment P35. The deoxyribonucleic acid of embodiment P34, wherein aplurality of methylation sites set forth in Table 2 are methylated orunmethylated.

Embodiment P36. A deoxyribonucleic acid chosen from SEQ ID NO:551 to SEQID NO:782, wherein said nucleic acid is hybridized to a complementaryDNA sequence comprising uridine or cytosine.

Embodiment P37. The deoxyribonucleic acid of embodiment P36, furthercomprising an enzyme in a complex with said hybridized complementary DNAsequence.

Embodiment P38. The deoxyribonucleic acid of embodiment P37, whereinsaid enzyme is Taq polymerase.

Embodiment P39. A kit comprising 322 nucleic acids each independentlycomprising SEQ ID NO:551 to SEQ ID NO:782, wherein said nucleic acids donot simultaneously comprise the same SEQ ID NO:551 to SEQ ID NO:782.

Embodiment P40. The kit according to embodiment P39, further comprising:enzymes, reagents for deamination of cytosine, buffers, vials, plasmidvectors, control DNA, devices for collecting thyroid tissue samples,reagents for isolating DNA, reagents for labeling DNA, or anycombinations thereof.

Embodiment P41. The kit according to embodiment P40, wherein the enzymesare selected from the group consisting of: thermostable DNA polymeraseenzymes, restriction enzymes, and combination thereof.

Further embodiments include embodiments 1-58 following.

Embodiment 1. A method of detecting methylation or unmethylation of athyroid nodule DNA molecule of a subject, the method comprising: (i)isolating a thyroid nodule DNA molecule from a thyroid nodule of saidsubject thereby forming an isolated thyroid nodule DNA molecule, (ii)contacting said isolated thyroid nodule DNA molecule with a bisulfitesalt thereby forming a reacted thyroid nodule DNA molecule, (iii)detecting the presence or absence of uracil in said reacted thyroidnodule DNA molecule at a methylation site set forth in Table 1, therebydetecting methylation or unmethylation of said thyroid nodule DNAmolecule of said subject.

Embodiment 2. The method of embodiment Error! Reference source notfound., further comprising detecting the presence or absence of uracilin said reacted thyroid nodule DNA molecule at a plurality ofmethylation sites set forth in Table 1, wherein said methylation siteforms a part of said plurality of methylation sites.

Embodiment 3. The method of embodiment Error! Reference source notfound., the method further comprising: (i) isolating a plurality ofthyroid nodule DNA molecules from said thyroid nodule of said subjectthereby forming a plurality of isolated thyroid nodule DNA molecules,wherein said isolated thyroid nodule DNA molecule forms part of saidplurality of isolated thyroid nodule DNA molecules, (ii) contacting saidplurality of isolated thyroid nodule DNA molecules with said bisulfitesalt thereby forming a plurality of reacted thyroid nodule DNAmolecules, wherein said reacted thyroid nodule DNA molecule forms partof said plurality of reacted thyroid nodule DNA molecules, (iii)detecting the level of reacted thyroid nodule DNA molecules in saidplurality of reacted thyroid nodule DNA molecules having a uracil at amethylation site set forth in Table 1, thereby detecting the level ofmethylation or unmethylation in said plurality of thyroid nodule DNAmolecules of said subject.

Embodiment 4. The method of embodiment Error! Reference source notfound., further comprising determining the level of uracil in saidreacted thyroid nodule DNA molecule at a plurality methylation sites setforth in Table 1, wherein said methylation site forms a part of saidplurality of methylation sites.

Embodiment 5. The method of embodiment Error! Reference source notfound., wherein said uracil level is above a threshold as set forth inTable 2.

Embodiment 6. The method of embodiment Error! Reference source notfound., wherein said uracil level is above a threshold as set forth inTable 3.

Embodiment 7. The method of embodiment Error! Reference source notfound., wherein said uracil level is below a threshold as set forth inTable 4.

Embodiment 8. The method of one of the above embodiments, wherein saidsubject is suspected of having thyroid cancer.

Embodiment 9. The method of one of the above embodiments, wherein saidthyroid nodule is a specimen obtained by biopsy or by surgical resectionof said subject.

Embodiment 10. The method of one of the above embodiments, wherein saidsubject has undergone thyroid surgery, radiation therapy, radioactiveiodine therapy, chemotherapy, thyroid hormone therapy, and/oradministration of an active agent.

Embodiment 11. The method of embodiment Error! Reference source notfound., wherein said active agent is chosen from Cabozantinib-S-Malate,Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate), DoxorubicinHydrochloride, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate),Nexavar (Sorafenib Tosylate), Sorafenib Tosylate, and/or Vandetanib.

Embodiment 12. A method of detecting a thyroid cancer or risk ofdeveloping thyroid cancer in a subject in need thereof, said methodcomprising:

-   (i) isolating a thyroid nodule DNA molecule from a thyroid nodule of    said subject thereby forming an isolated thyroid nodule DNA    molecule;-   (ii) contacting said isolated thyroid nodule DNA molecule with a    bisulfite salt thereby forming a reacted thyroid nodule DNA    molecule; and-   (iii) detecting the presence or absence of uracil in said reacted    thyroid nodule DNA molecule at a methylation site set forth in Table    1; thereby detecting said thyroid cancer in said subject.

Embodiment 13. The method of embodiment Error! Reference source notfound., wherein said subject (a) is a woman; (b) is about 20 to about 55years old; (c) has a mutated Ret Proto-Oncogene; (d) has a grandparent,parent, or sibling who has been diagnosed with thyroid cancer; (e)self-identifies as being Caucasian or Asian; and/or (f) has or has hadbreast cancer.

Embodiment 14. The method of embodiment Error! Reference source notfound., further comprising detecting the presence or absence of uracilin said reacted thyroid nodule DNA molecule at a plurality ofmethylation sites set forth in Table 1, wherein said methylation siteforms a part of said plurality of methylation sites.

Embodiment 15. The method of embodiment Error! Reference source notfound., the method further comprising: (i) isolating a plurality ofthyroid nodule DNA molecules from said thyroid nodule of said subjectthereby forming a plurality of isolated thyroid nodule DNA molecules,wherein said isolated thyroid nodule DNA molecule forms part of saidplurality of isolated thyroid nodule DNA molecules, (ii) contacting saidplurality of isolated thyroid nodule DNA molecules with said bisulfitesalt thereby forming a plurality of reacted thyroid nodule DNAmolecules, wherein said reacted thyroid nodule DNA molecule forms partof said plurality of reacted thyroid nodule DNA molecules, (iii)detecting the level of reacted thyroid nodule DNA molecules in saidplurality of reacted thyroid nodule DNA molecules having a uracil at amethylation site set forth in Table 1; thereby detecting said thyroidcancer in said subject.

Embodiment 16. The method of embodiment Error! Reference source notfound., further comprising determining the level of uracil in saidreacted thyroid nodule DNA molecule at a plurality methylation sites setforth in Table 1, wherein said methylation site forms a part of saidplurality of methylation sites.

Embodiment 17. The method of embodiment Error! Reference source notfound., wherein said uracil level is above a threshold as set forth inTable 2.

Embodiment 18. The method of embodiment Error! Reference source notfound., wherein said uracil level is above a threshold as set forth inTable 3.

Embodiment 19. The method of embodiment Error! Reference source notfound., wherein said uracil level is below a threshold as set forth inTable 4.

Embodiment 20. The method of one of the above embodiments, wherein saidsubject is suspected of having thyroid cancer.

Embodiment 21. The method of one of the above embodiments, wherein saidthyroid nodule is a specimen obtained by biopsy or by surgical resectionof said subject.

Embodiment 22. The method of one of the above embodiments, wherein saidsubject has undergone thyroid surgery, radiation therapy, radioactiveiodine therapy, chemotherapy, thyroid hormone therapy, andadministration of an active agent, before said determination.

Embodiment 23. The method of embodiment Error! Reference source notfound., wherein said active agent is chosen from Cabozantinib-S-Malate,Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate), DoxorubicinHydrochloride, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate),Nexavar (Sorafenib Tosylate), Sorafenib Tosylate, and.

Embodiment 24. A method of treating thyroid cancer in a subjectdetermined by the method as set forth in any of embodiments 12 to 23,comprising administering to said subject an active agent for treatingthyroid cancer.

Embodiment 25. The method of embodiment Error! Reference source notfound., wherein said subject has undergone surgery, radiation therapy,radioactive iodine therapy, chemotherapy, or thyroid hormone therapy,before said detection of claim Error! Reference source not found. at(iii).

Embodiment 26. The method of embodiment Error! Reference source notfound., wherein said active agent is chosen from Cabozantinib-S-Malate,Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate), DoxorubicinHydrochloride, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate),Nexavar (Sorafenib Tosylate), Sorafenib Tosylate, and Vandetanib.

Embodiment 27. The method of one of the above embodiments, wherein saidsubject has or is at risk of papillary thyroid cancer, follicularthyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer.

Embodiment 28. The method of one of the above embodiments, wherein saidbisulfite salt is sodium bisulfite.

Embodiment 29. The method of one of the above embodiments, furthercomprising determining a papillary thyroid carcinoma (PTC) methylationalteration score for said subject, wherein the PTC methylationalteration score is equal to: the number of methylation sites in Table 1having a uracil level equal to or greater than the correspondingthreshold level set forth in Table 2.

Embodiment 30. The method of one of the above embodiments, furthercomprising determining a benign thyroid nodule (BTN) methylationalteration score for said subject, wherein the BTN methylationalteration score is equal to:

-   (a) the number of methylation sites in Table 1 having a uracil level    equal to or greater than the corresponding threshold level set forth    in Table 3;-   (b) the number of methylation sites in Table 1 having a uracil level    equal to or less than the corresponding threshold level set forth in    Table 4; or-   (c) the number of methylation sites in Table 1 having a uracil level    equal to or greater than the corresponding threshold level set forth    in Table 3 plus the number of methylation sites in Table 1 having a    uracil level equal to or less than the corresponding threshold level    set forth in Table 4.

Embodiment 31. The method of embodiment Error! Reference source notfound., further comprising calculating a Composite Cancer Risk Score forsaid subject.

Embodiment 32. The method of embodiment Error! Reference source notfound., wherein said Composite Cancer Risk Score for said subjectequals:

$\begin{array}{l}{\left\lbrack {\text{the PTC methylation alteration score for said}\left( \text{subject} \right\rbrack} \right)/} \\{\left\lbrack \text{BTN methylation alteration score for said subject} \right\rbrack.}\end{array}$

Embodiment 33. The method of embodiment Error! Reference source notfound., wherein said Composite Cancer Risk Score for said subjectequals:

$\begin{array}{l}{\left\lbrack {\left( \text{the PTC methylation alteration score for said subject} \right) + 1} \right\rbrack/} \\{\left\lbrack {\left( \text{BTN methylaton alteration score for said subject} \right) + 1} \right\rbrack.}\end{array}$

Embodiment 34. The method of one of embodiments 29 to 33, wherein saidsubject is identified as being at risk of developing thyroid cancer ordiagnosed as having thyroid cancer if (a) the PTC methylation alterationscore for said subject is at least 5, 6, 7, 8, 9, or 10; (b) the BTNmethylation alteration score for said subject is at least 5, 6, 7, 8, 9,or 10; and/or (c) the Composite Cancer Risk Score for said subject is atleast about 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0.

Embodiment 35. The method of one of embodiments 29 to 33, wherein saidsubject is treated for thyroid cancer or directed to receive additionalscreening for thyroid cancer if (a) the PTC methylation alteration scorefor said subject is at least 5, 6, 7, 8, 9, or 10; (b) the BTNmethylation alteration score for said subject is at least 5, 6, 7, 8, 9,or 10; and/or (c) the Composite Cancer Risk Score for said subject is atleast about 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0.

Embodiment 36. A deoxyribonucleic acid at least 5 to 100 nucleotides inlength comprising a uracil-containing sequence that is identical to asequence of at least a 5 contiguous nucleotides within a sequence chosenfrom SEQ ID NO:1 to SEQ ID NO:550.

Embodiment 37. The deoxyribonucleic acid of embodiment 36, comprising auracil-containing sequence that is identical to a sequence of at least5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100,100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180,180-190, or 190-200 contiguous nucleotides within said sequence chosenfrom SEQ ID NO:1 to SEQ ID NO:550.

Embodiment 38. The deoxyribonucleic acid of embodiment 36 or 37, whereinsaid sequence comprises a methylation site set forth in Table 1.

Embodiment 39. The deoxyribonucleic acid of one of embodiments 36 to 38,wherein a plurality of methylation sites set forth in Table 1 contain auracil or a cytosine.

Embodiment 40. A deoxyribonucleic acid chosen from SEQ ID NO:551 to SEQID NO:782, wherein said nucleic acid is hybridized to a complementaryDNA sequence comprising uridine or cytosine.

Embodiment 41. The deoxyribonucleic acid of embodiment Error! Referencesource not found., further comprising an enzyme in a complex with saidhybridized complementary DNA sequence.

Embodiment 42. The deoxyribonucleic acid of embodiment Error! Referencesource not found., wherein said enzyme is Taq polymerase.

Embodiment 43. A kit comprising a plurality of nucleic acids eachindependently comprising SEQ ID NO:551 to SEQ ID NO:782, wherein eachnucleic acid of said plurality is unique.

Embodiment 44. The kit according to embodiment Error! Reference sourcenot found., further comprising: an enzyme, a reagent for deamination ofcytosine, a buffer, a vial, a plasmid vector, a control DNA, a devicefor collecting a thyroid tissue sample, a reagent for isolating DNA, areagent for labeling DNA, or any combination thereof.

Embodiment 45. The kit according to embodiment Error! Reference sourcenot found., wherein the enzyme comprises a thermostable DNA polymeraseenzyme and/or a restriction enzyme.

Embodiment 46. A system for detecting methylation or unmethylation of athyroid nodule deoxyribonucleic acid (DNA) of a subject, the systemcomprising:

-   at least one processor; and-   at least one memory including program code which when executed by    the at least one memory provides operations comprising:    -   isolating a thyroid nodule DNA molecule from a thyroid nodule of        said subject thereby forming an isolated thyroid nodule DNA        molecule;    -   contacting said isolated thyroid nodule DNA molecule with a        bisulfite salt thereby forming a reacted thyroid nodule DNA        molecule;    -   detecting the presence or absence of uracil in said reacted        thyroid nodule DNA molecule at a methylation site set forth in        Table 1, thereby detecting methylation or unmethylation of said        thyroid nodule DNA molecule of said subject;    -   generating a diagnosis for said subject based at least in part        on the presence or absence of uracil in said reacted thyroid        nodule DNA molecule at the methylation site set forth in Table        1; and    -   providing, via a user interface, the diagnosis for said subject.

Embodiment 47. The system of embodiment Error! Reference source notfound., wherein the system is further configured to detect the presenceor absence of uracil in said reacted thyroid nodule DNA molecule at aplurality of methylation sites set forth in Table 1, wherein saidmethylation site forms a part of said plurality of methylation sites.

Embodiment 48. The system of embodiment Error! Reference source notfound., wherein the system is further configured to: (i) isolate aplurality of thyroid nodule DNA molecules from said thyroid nodule ofsaid subject thereby forming a plurality of isolated thyroid nodule DNAmolecules, wherein said isolated thyroid nodule DNA molecule forms partof said plurality of isolated thyroid nodule DNA molecules, (ii) contactsaid plurality of isolated thyroid nodule DNA molecules with saidbisulfite salt thereby forming a plurality of reacted thyroid nodule DNAmolecules, wherein said reacted thyroid nodule DNA molecule forms partof said plurality of reacted thyroid nodule DNA molecules, (iii) detectthe level of reacted thyroid nodule DNA molecules in said plurality ofreacted thyroid nodule DNA molecules having a uracil at a methylationsite set forth in Table 1, thereby detecting the level of methylation orunmethylation in said plurality of thyroid nodule DNA molecules of saidsubject.

Embodiment 49. The system of embodiment Error! Reference source notfound., wherein the system is further configured to detect the level ofuracil in said reacted thyroid nodule DNA molecule at a pluralitymethylation sites set forth in Table 1, wherein said methylation siteforms a part of said plurality of methylation sites.

Embodiment 50. The system of embodiment Error! Reference source notfound., wherein said uracil level is above a threshold as set forth inTable 2.

Embodiment 51. The system of embodiment Error! Reference source notfound., wherein said uracil level is above a threshold as set forth inTable 3.

Embodiment 52. The system of embodiment Error! Reference source notfound., wherein said uracil level is below a threshold as set forth inTable 4.

Embodiment 53. The system of embodiment Error! Reference source notfound., wherein said subject is a candidate thyroid cancer patient.

Embodiment 54. The system of one of embodiments 46 to 53, wherein saidthyroid nodule is a specimen obtained by biopsy or by surgical resectionof said subject.

Embodiment 55. The system of one of embodiments 46 to 54, wherein saidsubject has undergone thyroid surgery, radiation therapy, radioactiveiodine therapy, chemotherapy, thyroid hormone therapy, and/oradministration of an active agent.

Embodiment 56. The system of embodiment Error! Reference source notfound., wherein said active agent is chosen from Cabozantinib-S-Malate,Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate), DoxorubicinHydrochloride, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate),Nexavar (Sorafenib Tosylate), Sorafenib Tosylate, and Vandetanib.

Embodiment 57. The system of one of embodiments 46 to 56, wherein thesystem is further configured to:

-   formulate, based at least in part on the diagnosis, a treatment plan    for said subject; and-   provide, via the user interface, the treatment plan.

Embodiment 58. The system of embodiment Error! Reference source notfound., wherein the treatment plan includes one or more of thyroidsurgery, radiation therapy, radioactive iodine therapy, chemotherapy,thyroid hormone therapy, and administration of an active agent.

EXAMPLES Example 1

Human frozen specimens were blindly evaluated by a pathologist. In thestudy, 28 benign nodules and 40 thyroid cancer specimens were analyzed.

DNA Methylation Profiling

Genomic DNA was isolated by using a standard phenol/chloroformextraction approach followed by ethanol precipitation. Further, genomicDNA underwent Reduced Representation Bisulfite Sequencing (RRBS)procedure. RRBS DNA amplicons were paired-end sequenced by using Hiseq2500 (Illumina). For each sample, at least 15 million aligned reads wereobtained. BTN and PTC specific signatures were determined based oncytosines which are characterized by at least 5 sequencing reads in eachsample.

Identification of BTN Specific and PTC Specific DNA Methylation Changes

DNA methylation patterns were analyzed in 114 thyroid specimensincluding 28 benign nodules, 40 thyroid cancer, and 46 adjacent normalthyroid tissues, to identify the presence of thyroid cancer specific andbenign nodule specific signatures. After genome alignment, a search wasperformed for DNA regions which have BTN or PTC specific alterations.For identification of a DNA region with a BTN specific loss of DNAmethylation, DNA regions were identified which had a DNA methylationlevel in at least 6 out 28 that was at least 2-fold less than the levelof methylation in the same DNA region any analyzed PTC specimen; wherethe lowest value of DNA methylation at this DNA region among all PTCspecimens is 20% or higher (FIG. 1A). For identification of DNA regionswith BTN specific DNA methylation accumulation, the following criteriawere used: a level of DNA methylation in an individual BTN that is atleast 2-fold higher than the level of DNA methylation in the same DNAregion in any analyzed PTC; where the value of DNA methylation ofanalyzed BTN specimen is at least 20% or more greater (FIG. 1B). The BTNsignature includes DNA regions which were affected by DNA methylationloss in at least 6 out 28 analyzed BTN samples and regions which wereaffected by DNA methylation accumulation in at least 6 out 28 analyzedBTN samples.

Further, regions were determined which undergo PTC specific DNAmethylation alterations. The criteria for the identification of DNAregions with a PTC specific loss of DNA methylation, was: a level of DNAmethylation in 6 out of 46 PTC that is 2-fold less than in any analyzedadenoma and any normal matching tissue, where the lowest value of DNAmethylation in the region among all non-malignant specimens is 20% orhigher. The criteria for the identification of DNA regions with PTCspecific DNA methylation accumulation was a level of DNA methylation inan individual PTC that is at least 2-fold higher than the level ofmethylation in any analyzed adenoma and normal matching tissue, wherethe value of DNA methylation in analyzed PTC sample should be 20% orhigher . There were no DNA regions that were affected by DNA methylationaccumulation in at least 6 PTC out 46 analyzed PTC. Therefore, the PTCspecific DNA methylation signatures contain only DNA regions which areaffected by DNA methylation loss in at least 6 out 46 analyzed PTC.

The total number of identified DNA regions which fall in PTC specific orBTN specific signature is 258, which comprises DNA methylationinformation for 364 cytosines (FIG. 2A). There are 230 cytosines whichcharacterize the PTC signature and 134 cytosines characterizing the BTNsignature.

Evaluation of the cancer specific and benign specific changes revealedthat 10 out of 40 thyroid cancer specimens are characterized by few(less than 5) or no cancer specific changes, and 4 out 28 benign nodulesindicated very few (less than 5) benign specific changes (FIG. 2A).Since the approach described herein is based on the identification ofthe tissue specific alterations, these specimens were determined to be“epigenetically indeterminate.”

For specimens with a determinate epigenetic state, clustering analysisrevealed a strict separation of thyroid cancer from benign nodules basedon DNA methylation levels of cytosines associated with benign and cancerscores (FIG. 2B). Thus, the use of benign and cancer scores can providea unique thyroid nodule diagnostic tool.

Development of Diagnostic Panel Based on BTN/PTC Signature Scores

The data disclosed herein demonstrates that analysis of DNA methylationof one or more of 258 DNA regions can provide substantial informationregarding a presence of malignancy in thyroid samples. Therefore, DNAmethylation analysis within BTN and PTC signature can be used as a PTCdiagnostic tool. According to the data, PTC diagnosis can be made byusing both BTN and PTC signatures. Each signature can be a score basedon the number of specific alterations within the signature for eachindividual sample. For example, the number of BTN specific alterationswithin BTN signature DNA regions reflects a BTN signature score. At thesame time, the number of PTC specific alterations for DNA regions withinPTC signature group indicates PTC signature score.

In order to validate the approach disclosed herein and estimate anaccuracy of the proposed signatures, a statistical analysis wasperformed based on the leave-one-out-cross-validation technique.Specifically, cancer and benign scores were determined for eachindividual nodule by using benign and cancer signatures which weredeveloped based on DNA methylation patterns of the rest of samplesexcluding the testing sample. In order to predict benign and cancerscores for 68 nodules, 68 benign and cancer unique predictive signatureswere developed.

After cross-validation, DNA methylation signatures (score >=5) wereobserved in 80% (32 out 40) of thyroid cancers and 82% (23 out 28) ofbenign nodules (FIG. 3A). These specimens with a determinate epigeneticstate were used for the further analysis.

According to the cross-validation observations, both, benign andmalignant diagnostic scores provided accurate results for thyroid nodulediagnostics (FIG. 3A). However, a combining of benign and malignantscores into a cancer risk score is associated with even higherdiagnostic performance. The cancer risk score was calculated using thefollowing equation: Cancer Risk Score = (cancer score+1) / (benignscore+1)

According to the data herein, specimens with cancer risk score above 2.6represent thyroid cancer and specimens with cancer score below 2.6 arebenign nodules. Based on these criteria, all 23 nodules were correctlydiagnosed as benign and 30 out 32 thyroid malignancies were diagnosed asa cancer (FIG. 3B). Therefore, the test had a specificity of 100% and asensitivity of 94%, with a 100% positive predictive value (PPV) and a92% negative predictive value (NPV). These data suggest that DNAmethylation analysis of 258 DNA regions in thyroid specimens can serveas a potential diagnostic tool for the determination of malignancy.

An algorithm for performing a thyroid nodule diagnostic evaluation isshown in FIG. 3C. Specimens with benign and malignant signatures areassociated with indeterminate epigenetic state and were excluded fromthe study. Specimens with a cancer risk score above 2.6 are consideredto be malignant, and thyroid nodules with a cancer risk score below 2.6are considered to be benign.

This scoring approach clearly differentiates benign from malignantspecimens. These data suggest that DNA methylation analysis of 258 DNAregions in thyroid specimens, including potentially FNA specimens, canserve as a diagnostic tool for the determination of malignancy.

The data indicates that malignancy of thyroid specimens can bedetermined by DNA methylation pattern analysis of one or more of 258different DNA regions.

1-58. (canceled)
 59. A method of treating papillary thyroid cancer in asubject in need thereof, the method comprising: detecting 4 or morepapillary thyroid carcinoma (PTC) methylation sites above acorresponding uracil threshold level in an isolated DNA from a thyroidnodule from said subject as set forth in Table 2, wherein Table 2 isTABLE 2 Chromosome Chromosomal Position Uracil threshold level chr111979164 89.29 chr1 16450525 70.00 chr1 16450542 72.00 chr1 1645054573.33 chr1 16469987 80.00 chr1 17494491 86.00 chr1 25473203 88.89 chr138493013 86.36 chr1 38493030 79.17 chr1 38493074 80.95 chr1 10981609280.77 chr1 109816111 80.77 chr1 110074669 75.00 chr1 110074681 71.43chr1 110074685 63.16 chr1 150949856 89.29 chr1 150949857 88.46 chr1153540282 78.26 chr1 155162704 84.21 chr1 155162714 88.64 chr1 15761188183.05 chr1 182205324 77.50 chr1 204118999 59.09 chr1 206741875 83.33chr1 206741989 66.67 chr1 212841198 85.29 chr1 223403952 79.17 chr1234342767 76.67 chr10 3929071 88.68 chr10 30047012 86.84 chr10 7970298983.33 chr10 87984905 86.36 chr10 94838789 63.33 chr10 102131187 90.00chr10 104196489 75.00 chr10 111766879 89.47 chr10 112258886 81.82 chr10112258984 83.33 chr10 112259015 82.61 chr10 120011530 79.55 chr11 82128289.13 chr11 12188937 83.33 chr11 12188948 77.78 chr11 12188995 78.57chr11 65158294 78.00 chr11 65158342 85.00 chr11 65297089 75.00 chr1166104481 81.58 chr11 66104485 83.33 chr11 66104578 81.82 chr11 7023629289.29 chr11 70236320 85.71 chr11 70236331 70.83 chr11 117950310 79.55chr11 117950329 79.55 chr11 117950361 80.00 chr11 117950362 81.82 chr12679803 86.84 chr12 26039132 73.91 chr12 50286016 82.14 chr12 5224325882.00 chr12 52243286 82.50 chr12 56115043 89.29 chr12 66262229 72.22chr12 66262230 71.74 chr12 66262233 68.27 chr12 66262234 71.74 chr12117580102 84.62 chr12 123435962 63.89 chr12 123436011 71.88 chr12123436065 69.44 chr12 123540893 77.27 chr13 46771519 67.65 chr1346771520 73.91 chr14 38599118 65.91 chr14 69170010 86.36 chr14 7570163268.42 chr14 75701643 68.75 chr14 103768055 76.09 chr14 104354645 72.92chr14 104360487 83.33 chr15 41068807 69.12 chr15 61152225 83.33 chr1561152253 86.67 chr15 61152313 86.67 chr15 70667596 83.33 chr15 7076720690.00 chr15 77989064 73.53 chr15 85402496 82.10 chr15 85402497 79.49chr15 99417337 88.89 chr16 1231873 86.36 chr16 23135832 87.50 chr1629616265 85.71 chr16 31009547 84.00 chr16 31009548 85.00 chr16 3100959085.00 chr16 57793674 80.95 chr16 57793715 85.71 chr16 57793727 80.95chr16 70771056 68.75 chr16 70771079 63.33 chr16 70771141 65.79 chr1677332010 72.58 chr16 78540378 75.76 chr16 84262419 87.23 chr17 1632346085.00 chr17 16323473 84.21 chr17 16924561 80.36 chr17 16924562 75.71chr17 16924594 75.71 chr17 17717918 72.73 chr17 17718591 84.38 chr1718139506 82.81 chr17 39677570 71.88 chr17 43200096 77.78 chr17 4320023985.00 chr17 48178379 83.33 chr17 48764165 88.89 chr17 55701962 68.75chr17 73993165 90.00 chr17 75827716 78.57 chr17 76882243 61.54 chr1778765910 88.71 chr17 79544478 83.15 chr17 80696474 60.00 chr18 2144076067.86 chr18 45555437 66.18 chr18 45555438 73.68 chr18 46547891 76.09chr18 55888885 75.47 chr18 56452096 90.00 chr18 56452476 81.82 chr1876002973 81.58 chr18 77331090 81.03 chr19 677895 85.29 chr19 88404476.92 chr19 884059 76.92 chr19 884105 84.62 chr19 884115 84.62 chr191136511 86.96 chr19 1177605 73.68 chr19 1177612 72.73 chr19 117764081.82 chr19 1860601 88.46 chr19 1860607 82.81 chr19 2503954 90.00 chr194052713 85.56 chr19 4052714 85.14 chr19 4052749 84.62 chr19 437459182.14 chr19 5048836 77.27 chr19 5048867 70.59 chr19 5048877 73.53 chr198367279 75.00 chr19 10254577 76.25 chr19 10254578 79.17 chr19 1320367175.86 chr19 15375465 72.22 chr19 17218912 81.25 chr19 18157161 88.24chr19 18157221 86.76 chr19 18157258 65.22 chr19 30606642 80.56 chr1947316268 76.67 chr2 20412441 85.71 chr2 65064865 64.71 chr2 7082364179.03 chr2 74454110 70.00 chr2 128158884 85.00 chr2 128158910 77.50 chr2203114171 79.63 chr2 238341465 86.36 chr2 238341542 90.00 chr2 23834154687.50 chr2 238774763 67.57 chr20 31126186 87.50 chr20 31126189 84.21chr20 36771969 79.31 chr20 48993661 80.00 chr20 58406398 89.66 chr2061976049 87.93 chr20 61976073 89.66 chr22 19738127 70.59 chr22 3596517676.32 chr22 36549809 83.33 chr22 36973375 80.43 chr22 39662794 84.62chr22 45622980 85.00 chr3 14180153 57.89 chr3 52525100 79.41 chr362589658 87.50 chr3 65388317 71.43 chr3 65388388 79.31 chr3 7359930285.11 chr3 197093846 80.00 chr4 3743223 68.18 chr4 5755716 85.48 chr45755717 80.00 chr4 5755728 82.26 chr4 5755729 79.17 chr4 5755734 79.17chr4 57548289 80.23 chr5 1118280 73.08 chr5 34564389 89.29 chr5 7387190789.47 chr5 78013596 70.00 chr5 78013643 80.00 chr5 137802650 72.73 chr5139051189 84.09 chr5 167838221 68.18 chr6 7236568 84.43 chr6 4143857589.66 chr6 43464150 75.76 chr7 989235 76.67 chr7 2673543 82.14 chr7105079565 78.75 chr7 105079631 71.25 chr7 151425103 86.96 chr7 15142510476.19 chr8 11764017 80.77 chr8 141320393 75.00 chr8 141320410 85.00 chr96566568 86.84 chr9 126126741 86.11 chr9 136077410 73.91 chr9 13965501883.33 chr9 140205985 75.00 chr9 140205989 83.33 chr9 140205997 79.17

and wherein detection of 4 or more papillary thyroid carcinoma (PTC)methylation sites above a corresponding uracil threshold level in anisolated DNA from a thyroid nodule from said subject indicates thattreatment is required; and administering to said subject an active agentfor treating papillary thyroid cancer.
 60. The method of claim 59,wherein the method comprises detecting 5 or more papillary thyroidcarcinoma (PTC) methylation sites above a corresponding uracil thresholdlevel in an isolated DNA from a thyroid nodule from said subject as setforth in Table
 2. 61. The method of claim 59, wherein the method furthercomprises detecting 1 or more benign thyroid nodule (BTN) methylationsites, where each BTN methylation site is a methylation site which isabove a corresponding uracil threshold level in said isolated DNA as setforth in Table 3, wherein Table 3 is TABLE 3 Chromosome ChromosomalPosition Uracil threshold level chr1 2996653 88.84 chr1 27640460 80.56chr10 126172714 80.00 chr10 126172747 84.62 chr11 36057726 79.63 chr1148070143 84.38 chr11 48070163 87.50 chr11 48070166 84.38 chr11 4807017484.48 chr12 77266621 73.53 chr14 97524282 88.89 chr14 104209000 80.77chr14 104209068 83.33 chr15 77984014 88.89 chr16 3023231 84.00 chr1679333435 89.61 chr17 1509928 88.46 chr17 1509945 88.46 chr17 150995283.93 chr17 1509953 85.00 chr17 7644013 85.42 chr17 48596391 88.64 chr195013982 83.33 chr19 10463956 86.73 chr19 10464137 89.29 chr19 4717303788.64 chr2 3454277 84.78 chr2 8793724 78.57 chr2 55289272 75.00 chr2122014529 86.36 chr2 218221671 85.19 chr22 38307317 89.66 chr4 837286185.71 chr6 3394325 87.84 chr6 3887581 85.71 chr6 1.59E+08 86.84 chr822548399 88.16 chr8 22548483 87.50 chr8 1.34E+08 80.00 chr9 1619786286.36

.
 62. The method of claim 59, wherein the method further comprisesdetecting a methylation site which is below a corresponding uracilthreshold level in said isolated DNA as set forth in Table 4, whereinTable 4 is TABLE 4 Chromosome Chromosomal Position Uracil thresholdlevel chr1 12655938 69.23 chr1 29565080 60.00 chr1 46713777 73.33 chr146914121 60.00 chr1 46955744 77.78 chr1 55008344 60.00 chr1 15667661184.62 chr1 212587673 80.00 chr1 233430972 86.67 chr10 116391763 75.00chr11 556355 75.00 chr11 68608767 73.33 chr11 115530032 79.49 chr11119293593 60.00 chr12 31004558 81.82 chr12 45610695 83.33 chr12 4561070186.67 chr12 45610702 89.47 chr12 45610706 80.00 chr12 54145732 82.35chr12 54145741 76.47 chr12 54145825 70.59 chr13 20735797 82.35 chr1323500419 68.42 chr13 53313426 60.00 chr13 113807393 27.27 chr14 9085045454.55 chr14 103541602 52.00 chr15 65186440 55.56 chr15 68851629 63.64chr15 75251486 60.00 chr15 83952081 72.73 chr16 1458639 75.00 chr1688701114 66.67 chr16 89988308 83.33 chr16 89988644 47.37 chr17 3527803128.42 chr17 40826257 23.81 chr17 43037426 33.33 chr17 43510142 81.82chr17 47987828 69.23 chr17 73584599 60.00 chr18 19751759 33.33 chr1856887181 60.00 chr19 3434917 40.00 chr19 3434921 42.86 chr19 343493057.14 chr19 3434939 71.43 chr19 3434952 71.43 chr19 3434954 60.00 chr193434962 71.43 chr19 3434964 71.43 chr19 3434979 66.67 chr19 343498555.56 chr19 8428573 75.00 chr19 13266925 66.67 chr19 13266934 66.67chr19 13266970 63.64 chr19 13842142 76.47 chr19 14248494 73.91 chr1917346702 85.71 chr19 17346735 78.95 chr19 18415877 47.83 chr19 1841589047.83 chr19 35531842 83.33 chr19 44303112 77.78 chr19 47778278 66.67chr19 47778298 83.33 chr2 42329402 78.95 chr2 42329494 60.00 chr273143689 77.78 chr2 219745335 81.82 chr20 34206950 76.47 chr20 6258857150.00 chr20 62588579 38.46 chr22 37447953 73.33 chr22 37914998 69.23chr3 13323642 72.73 chr3 45209073 60.00 chr3 45209207 83.33 chr3195636893 84.62 chr5 177541401 69.23 chr5 180018672 72.73 chr5 18010102664.71 chr6 7728692 73.33 chr6 34203617 45.45 chr6 37751320 78.57 chr641410682 77.78 chr6 41438516 39.13 chr7 73508602 85.71 chr8 2164730871.43 chr9 34591313 80.00 chr9 98225096 22.22 chr9 132083428 70.59

.
 63. The method of claim 59, wherein the isolated DNA is obtained bybiopsy or by surgical resection of said subject.
 64. The method of claim63, wherein the subject (a) is a woman; (b) is about 20 to about 55years old; (c) has a mutated Ret Proto-Oncogene; (d) has a grandparent,parent, or sibling who has been diagnosed with thyroid cancer; (e)self-identifies as being Caucasian or Asian; and/or (f) has or has hadbreast cancer.
 65. The method of claim 59, wherein the subject hasundergone thyroid surgery, radiation therapy, radioactive iodinetherapy, chemotherapy, thyroid hormone therapy, and/or administration ofan active agent.
 66. The method of claim 59, wherein the active agent ischosen from Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq(Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate,Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate), SorafenibTosylate, and/or Vandetanib.
 67. A method of detecting methylation sitesin a subject, said method comprising detecting 4 or more papillarythyroid carcinoma (PTC) methylation sites above a corresponding uracilthreshold level as set forth in Table 2 in an isolated DNA from athyroid nodule from a subject having papillary thyroid cancer, whereinTable 2 is TABLE 2 Chromosome Chromosomal Position Uracil thresholdlevel chr1 11979164 89.29 chr1 16450525 70.00 chr1 16450542 72.00 chr116450545 73.33 chr1 16469987 80.00 chr1 17494491 86.00 chr1 2547320388.89 chr1 38493013 86.36 chr1 38493030 79.17 chr1 38493074 80.95 chr1109816092 80.77 chr1 109816111 80.77 chr1 110074669 75.00 chr1 11007468171.43 chr1 110074685 63.16 chr1 150949856 89.29 chr1 150949857 88.46chr1 153540282 78.26 chr1 155162704 84.21 chr1 155162714 88.64 chr1157611881 83.05 chr1 182205324 77.50 chr1 204118999 59.09 chr1 20674187583.33 chr1 206741989 66.67 chr1 212841198 85.29 chr1 223403952 79.17chr1 234342767 76.67 chr10 3929071 88.68 chr10 30047012 86.84 chr1079702989 83.33 chr10 87984905 86.36 chr10 94838789 63.33 chr10 10213118790.00 chr10 104196489 75.00 chr10 111766879 89.47 chr10 112258886 81.82chr10 112258984 83.33 chr10 112259015 82.61 chr10 120011530 79.55 chr11821282 89.13 chr11 12188937 83.33 chr11 12188948 77.78 chr11 1218899578.57 chr11 65158294 78.00 chr11 65158342 85.00 chr11 65297089 75.00chr11 66104481 81.58 chr11 66104485 83.33 chr11 66104578 81.82 chr1170236292 89.29 chr11 70236320 85.71 chr11 70236331 70.83 chr11 11795031079.55 chr11 117950329 79.55 chr11 117950361 80.00 chr11 117950362 81.82chr12 679803 86.84 chr12 26039132 73.91 chr12 50286016 82.14 chr1252243258 82.00 chr12 52243286 82.50 chr12 56115043 89.29 chr12 6626222972.22 chr12 66262230 71.74 chr12 66262233 68.27 chr12 66262234 71.74chr12 117580102 84.62 chr12 123435962 63.89 chr12 123436011 71.88 chr12123436065 69.44 chr12 123540893 77.27 chr13 46771519 67.65 chr1346771520 73.91 chr14 38599118 65.91 chr14 69170010 86.36 chr14 7570163268.42 chr14 75701643 68.75 chr14 103768055 76.09 chr14 104354645 72.92chr14 104360487 83.33 chr15 41068807 69.12 chr15 61152225 83.33 chr1561152253 86.67 chr15 61152313 86.67 chr15 70667596 83.33 chr15 7076720690.00 chr15 77989064 73.53 chr15 85402496 82.10 chr15 85402497 79.49chr15 99417337 88.89 chr16 1231873 86.36 chr16 23135832 87.50 chr1629616265 85.71 chr16 31009547 84.00 chr16 31009548 85.00 chr16 3100959085.00 chr16 57793674 80.95 chr16 57793715 85.71 chr16 57793727 80.95chr16 70771056 68.75 chr16 70771079 63.33 chr16 70771141 65.79 chr1677332010 72.58 chr16 78540378 75.76 chr16 84262419 87.23 chr17 1632346085.00 chr17 16323473 84.21 chr17 16924561 80.36 chr17 16924562 75.71chr17 16924594 75.71 chr17 17717918 72.73 chr17 17718591 84.38 chr1718139506 82.81 chr17 39677570 71.88 chr17 43200096 77.78 chr17 4320023985.00 chr17 48178379 83.33 chr17 48764165 88.89 chr17 55701962 68.75chr17 73993165 90.00 chr17 75827716 78.57 chr17 76882243 61.54 chr1778765910 88.71 chr17 79544478 83.15 chr17 80696474 60.00 chr18 2144076067.86 chr18 45555437 66.18 chr18 45555438 73.68 chr18 46547891 76.09chr18 55888885 75.47 chr18 56452096 90.00 chr18 56452476 81.82 chr1876002973 81.58 chr18 77331090 81.03 chr19 677895 85.29 chr19 88404476.92 chr19 884059 76.92 chr19 884105 84.62 chr19 884115 84.62 chr191136511 86.96 chr19 1177605 73.68 chr19 1177612 72.73 chr19 117764081.82 chr19 1860601 88.46 chr19 1860607 82.81 chr19 2503954 90.00 chr194052713 85.56 chr19 4052714 85.14 chr19 4052749 84.62 chr19 437459182.14 chr19 5048836 77.27 chr19 5048867 70.59 chr19 5048877 73.53 chr198367279 75.00 chr19 10254577 76.25 chr19 10254578 79.17 chr19 1320367175.86 chr19 15375465 72.22 chr19 17218912 81.25 chr19 18157161 88.24chr19 18157221 86.76 chr19 18157258 65.22 chr19 30606642 80.56 chr1947316268 76.67 chr2 20412441 85.71 chr2 65064865 64.71 chr2 7082364179.03 chr2 74454110 70.00 chr2 128158884 85.00 chr2 128158910 77.50 chr2203114171 79.63 chr2 238341465 86.36 chr2 238341542 90.00 chr2 23834154687.50 chr2 238774763 67.57 chr20 31126186 87.50 chr20 31126189 84.21chr20 36771969 79.31 chr20 48993661 80.00 chr20 58406398 89.66 chr2061976049 87.93 chr20 61976073 89.66 chr22 19738127 70.59 chr22 3596517676.32 chr22 36549809 83.33 chr22 36973375 80.43 chr22 39662794 84.62chr22 45622980 85.00 chr3 14180153 57.89 chr3 52525100 79.41 chr362589658 87.50 chr3 65388317 71.43 chr3 65388388 79.31 chr3 7359930285.11 chr3 197093846 80.00 chr4 3743223 68.18 chr4 5755716 85.48 chr45755717 80.00 chr4 5755728 82.26 chr4 5755729 79.17 chr4 5755734 79.17chr4 57548289 80.23 chr5 1118280 73.08 chr5 34564389 89.29 chr5 7387190789.47 chr5 78013596 70.00 chr5 78013643 80.00 chr5 137802650 72.73 chr5139051189 84.09 chr5 167838221 68.18 chr6 7236568 84.43 chr6 4143857589.66 chr6 43464150 75.76 chr7 989235 76.67 chr7 2673543 82.14 chr7105079565 78.75 chr7 105079631 71.25 chr7 151425103 86.96 chr7 15142510476.19 chr8 11764017 80.77 chr8 141320393 75.00 chr8 141320410 85.00 chr96566568 86.84 chr9 126126741 86.11 chr9 136077410 73.91 chr9 13965501883.33 chr9 140205985 75.00 chr9 140205989 83.33 chr9 140205997 79.17

and wherein detection of 4 or more papillary thyroid carcinoma (PTC)methylation sites above a corresponding uracil threshold level in anisolated DNA from a thyroid nodule from said subject indicates that thesubject has papillary thyroid cancer or is at risk of developingpapillary thyroid cancer; and administering to said subject an activeagent for treating papillary thyroid cancer.
 68. The method of claim 67,wherein the method comprises detecting 5 or more papillary thyroidcarcinoma (PTC) methylation sites above a corresponding uracil thresholdlevel in an isolated DNA from a thyroid nodule from said subject as setforth in Table
 2. 69. The method of claim 67, wherein the method furthercomprises detecting 1 or more benign thyroid nodule (BTN) methylationsites, where each BTN methylation site is (i) a methylation site whichis above a corresponding threshold level as set forth in Table 3,wherein Table 3 is TABLE 3 Chromosome Chromosomal Position Uracilthreshold level chr1 2996653 88.84 chr1 27640460 80.56 chr10 12617271480.00 chr10 126172747 84.62 chr11 36057726 79.63 chr11 48070143 84.38chr11 48070163 87.50 chr11 48070166 84.38 chr11 48070174 84.48 chr1277266621 73.53 chr14 97524282 88.89 chr14 104209000 80.77 chrl4104209068 83.33 chrl5 77984014 88.89 chrl6 3023231 84.00 chrl6 7933343589.61 chrl7 1509928 88.46 chrl7 1509945 88.46 chrl7 1509952 83.93 chrl71509953 85.00 chrl7 7644013 85.42 chrl7 48596391 88.64 chr19 501398283.33 chr19 10463956 86.73 chr19 10464137 89.29 chr19 47173037 88.64chr2 3454277 84.78 chr2 8793724 78.57 chr2 55289272 75.00 chr2 12201452986.36 chr2 218221671 85.19 chr22 38307317 89.66 chr4 8372861 85.71 chr63394325 87.84 chr6 3887581 85.71 chr6 1.59E+08 86.84 chr8 22548399 88.16chr8 22548483 87.50 chr8 1.34E+08 80.00 chr9 16197862 86.36

.
 70. The method of claim 67, wherein the method further comprisesdetecting a methylation site which is below a corresponding thresholdlevel as set forth in Table 4, wherein Table 4 is TABLE 4 ChromosomeChromosomal Position Uracil threshold level chr1 12655938 69.23 chr129565080 60.00 chr1 46713777 73.33 chr1 46914121 60.00 chr1 4695574477.78 chr1 55008344 60.00 chr1 156676611 84.62 chr1 212587673 80.00 chr1233430972 86.67 chr10 116391763 75.00 chr11 556355 75.00 chr11 6860876773.33 chr11 115530032 79.49 chr11 119293593 60.00 chr12 31004558 81.82chr12 45610695 83.33 chr12 45610701 86.67 chr12 45610702 89.47 chr1245610706 80.00 chr12 54145732 82.35 chr12 54145741 76.47 chr12 5414582570.59 chr13 20735797 82.35 chr13 23500419 68.42 chr13 53313426 60.00chr13 113807393 27.27 chr14 90850454 54.55 chr14 103541602 52.00 chr1565186440 55.56 chr15 68851629 63.64 chr15 75251486 60.00 chr15 8395208172.73 chr16 1458639 75.00 chr16 88701114 66.67 chr16 89988308 83.33chr16 89988644 47.37 chr17 35278031 28.42 chr17 40826257 23.81 chr1743037426 33.33 chr17 43510142 81.82 chr17 47987828 69.23 chr17 7358459960.00 chr18 19751759 33.33 chr18 56887181 60.00 chr19 3434917 40.00chr19 3434921 42.86 chr19 3434930 57.14 chr19 3434939 71.43 chr193434952 71.43 chr19 3434954 60.00 chr19 3434962 71.43 chr19 343496471.43 chr19 3434979 66.67 chr19 3434985 55.56 chr19 8428573 75.00 chr1913266925 66.67 chr19 13266934 66.67 chr19 13266970 63.64 chr19 1384214276.47 chr19 14248494 73.91 chr19 17346702 85.71 chr19 17346735 78.95chr19 18415877 47.83 chr19 18415890 47.83 chr19 35531842 83.33 chr1944303112 77.78 chr19 47778278 66.67 chr19 47778298 83.33 chr2 4232940278.95 chr2 42329494 60.00 chr2 73143689 77.78 chr2 219745335 81.82 chr2034206950 76.47 chr20 62588571 50.00 chr20 62588579 38.46 chr22 3744795373.33 chr22 37914998 69.23 chr3 13323642 72.73 chr3 45209073 60.00 chr345209207 83.33 chr3 195636893 84.62 chr5 177541401 69.23 chr5 18001867272.73 chr5 180101026 64.71 chr6 7728692 73.33 chr6 34203617 45.45 chr637751320 78.57 chr6 41410682 77.78 chr6 41438516 39.13 chr7 7350860285.71 chr8 21647308 71.43 chr9 34591313 80.00 chr9 98225096 22.22 chr9132083428 70.59

.
 71. The method of claim 67, wherein the isolated DNA is obtained bybiopsy or by surgical resection of the subject.
 72. The method of claim71, wherein the subject (a) is a woman; (b) is about 20 to about 55years old; (c) has a mutated Ret Proto-Oncogene; (d) has a grandparent,parent, or sibling who has been diagnosed with thyroid cancer; (e)self-identifies as being Caucasian or Asian; and/or (f) has or has hadbreast cancer.
 73. The method of claim 67, wherein the active agent ischosen from Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq(Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate,Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate), SorafenibTosylate, and/or Vandetanib.